There have been a number of cases reported in the medical literature indicating a link between herbal consumption and adverse effects. Many of these are reviewed in the monographs in this book. Most are minor and infrequent in nature. Where serious adverse events are reported, the information is often of poor quality, making a credible link between cause and effect difficult to establish. However, it is worthwhile to note some defining examples of serious adverse events that have occurred in the past few decades. Many of these have resulted from contamination or adulteration, or relate to known toxic herbs.

During the early 1990s, several patients with renal failure were admitted to hospitals in Brussels with progressive interstitial fibrosis and tubular atrophy that was linked to a herbal slimming preparation. At least 30 individuals were found to have sustained end-stage renal failure from the incident, making it perhaps the single most serious adverse event linked to herbal consumption in modern times. The Chinese herb Aristolochia fangchi was found to be an ingredient of the formulation instead of the intended Stephania tetrandra. The consequent presence of aristolochic acid, a known toxin, was put forward as a hypothesis for the aetiology of the nephropathies in the literature and the phenomenon became known (perhaps incorrectly) as Chinese herb nephropathy (CHN). However, the case prompted the Association Pharmaceutique Belge at the Service du Contrôle des Médicaments to probe the matter further.³ They pointed to the idiosyncratic nature of the reactions and the presence of other powerful synthetic drugs in the mixture as suggesting a more complex story. They considered that the cocktail of sometimes powerful preparations adopted by some observing slimming regimes might have significantly lowered the threshold for renal damage. However, aristolochic acid has been known as a nephrotoxin for decades and cases not linked to the concurrent use of drugs have been reported.⁴

In 1997, it was reported that two of the women subsequently developed urothelial cancer caused by the genotoxicity of aristolochic acid.⁵ An article published in June 1999 reported further cases of urothelial cancer. Cosyns and co-workers tested 10 patients with CHN.⁶ Four (40%) were found to have urothelial carcinoma and abnormal cells were found in all of the 10 patients. Nortier and co-workers⁷ (June 2000) concluded that the incidence of urothelial cancer among patients with CHN is high and that the risk was related to the cumulative dose of the herb. They reported treating 105 patients with CHN of whom 43 had been admitted with end-stage renal failure. Thirty-nine of these patients were tested for urothelial carcinoma. Eighteen cases were found, and mild-to-moderate dysplasia was found in a further 19 patients.

Cases of CHN have also been reported in France, Spain, Japan, the UK and Taiwan, where cases of urothelial carcinoma have also been detected.⁷Aristolochia spp. can also be used as substitutes for several other Chinese herbs,⁸ and Chinese herbal products found to contain aristolochic acid have been recalled in several countries (including Australia⁹ and the USA¹⁰).

This is the first credible, real-world example where the clinical use of a medicinal plant (albeit not the intended one) has resulted in the subsequent development of cancer.

During the early 1990s, liver units in France began to report a number of cases of liver disease possibly linked to the consumption of a slimming herb. The hepatotoxicity of germander (Teucrium chamaedrys) was confirmed in isolated rat hepatocytes, particularly a crude fraction containing the diverse furanoditerpenoids. It was concluded that they are activated by cytochrome P450 3 A into electrophilic metabolites that deplete glutathione and protein thiols and form plasma membrane blebs.¹¹ However, these cases were more likely to have been idiosyncratic drug reactions (IDRs) to the germander. Germander was subsequently banned from use in many countries, although germander-induced hepatotoxicity is probably still occurring, mainly from the fact that certain species of Teucrium are commonly used as a substitute for American skullcap (Scutellaria lateriflora).

In fact, so widespread was this adulteration, the macroscopic and microscopic description of skullcap cut herb in the British Herbal Pharmacopoeia 1983 was probably for a species of Teucrium. Adulteration of commercial skullcap continued to be an issue in Europe, the UK and the USA into the late 20th century.¹² Idiosyncratic hepatotoxicity was reported for tablets containing skullcap and valerian in 1989¹³ and for tablets containing skullcap, mistletoe, kelp, wild lettuce and motherwort in 1981¹⁴ (although the presence of mistletoe was later questioned).¹⁵ The observed hepatotoxicity of these herbal products is probably attributable to a germander species, rather than the herbs mentioned, including skullcap. Case reports of hepatotoxicity caused by germander are not limited to T. chamaedrys,¹⁶ other Teucrium spp. have caused hepatic failure.¹⁷ One of the reported UK cases of skullcap-related hepatotoxicity was confirmed as being due to T. canadense rather than skullcap.¹⁶

From January 1991 to December 1993, the Medical Toxicology Unit (formerly Poisons Unit) at Guy’s and St Thomas’s Hospital in London received reports of 11 cases of liver damage following the use of Chinese herbal medicine for skin conditions. There was strong evidence of an association in two cases, as recovery after withdrawal and recurrence of hepatitis after rechallenge were observed. The time-course relationship, recovery after ceasing Chinese herbal medicine and absence of alternative causes of liver damage suggested an association in two further symptomatic cases following a single period of exposure. Herbal material was available for analysis in seven cases. The plant mixtures varied, so no single ingredient could account for liver injury. Effects did not appear dose related and it was concluded they were probably idiosyncratic.¹⁸ Two patients were additionally described who suffered an acute hepatic illness related to taking traditional Chinese herbs for skin disease. Both recovered fully. The mixtures they took included two herbs that were also present in the mixture taken by a previously reported patient who suffered fatal hepatic necrosis.¹⁹ Sporadic cases of IDRs to Chinese herbal formulations resulting in hepatotoxicity have been reported in the literature ever since. A 2009 study from a gastroenterological department in a Chinese hospital concluded that Chinese herbs were a significant factor in idiosyncratic hepatotoxicity, although the liver injury was not severe in most cases.²⁰ Other studies reviewing patients attending single clinics or hospitals in the UK, Germany and Japan have found a much lower incidence of idiosyncratic hepatitis from the use of Chinese herbal formulations.²¹

Case reports of idiosyncratic hepatotoxicity to Western herbs extend beyond germander. A review of 18 reports of adverse events associated with the ingestion of chaparral reported to the Food and Drug Administration (FDA) between 1992 and 1994 found evidence of hepatotoxicity in 13 cases (causal (10), not followed up (1), probable (2), insufficient data (5)). Of the 13 cases, 10 had ingested chaparral only, with the remainder taking products containing chaparral and other herbs and/or ingredients. Adverse events occurred 3 to 52 weeks after the ingestion of chaparral and resolved 1 to 17 weeks after ceasing intake. The predominant pattern of liver injury was characterised as toxic or drug-induced cholestatic hepatitis. In four individuals there was progression to cirrhosis and in two individuals there was acute fulminant liver failure that required a liver transplant. Of the patients requiring a liver transplant, chaparral was probably not the only factor in one case.²²

In November 2001 the German Health Authority (BfArM) announced that it was intending to ban the use of kava (Piper methysticum) because of reported cases linking kava consumption with hepatotoxicity. Despite submissions from manufacturers, the therapeutic use of kava was banned altogether in Germany in 2002 and several other countries such as Japan, France and Canada followed suit. Late in 2002 it was announced that the Medicines Control Agency (MCA) in the UK would also be banning kava; in February 2003 Swissmedic in Switzerland followed. Like most other herbal hepatotoxicity cases, those linked to kava usage were most likely an immunologically mediated IDR ca rather than a direct toxic effect. Issues associated with this potential IDR to kava are fully explored in the kava monograph.

In 2002 a group of Australian doctors reported suspected hepatotoxicity, presumably an IDR, associated with the ingestion of black cohosh (Actaea racemosa).²³ At least 68 more cases have been reported since then, but the association remains a contentious issue. One analysis of the reported cases using the updated Council for International Organisations of Medical Sciences (CIOMS) causality assessment asserted that there was little, if any, evidence for a causal relationship between use of black cohosh and liver damage.²⁴ For more information on this topic see the black cohosh monograph.

Since its widespread promotion and use in the USA, numerous adverse reactions to the herb Ephedra (Ephedra sinica) have been recorded. However, it is difficult to assess meaningfully the majority of these due to insufficient information, the failure to distinguish between its main alkaloid ephedrine and Ephedra as treatments, and the tendency to combine Ephedra with other stimulants in weight loss products (which may potentiate its ability to cause serious side effects).

Nonetheless, the RAND Report undertook a comprehensive analysis of adverse consequences from both clinical trials and case reports submitted to the FDA.²⁵ Using data from clinical trials, the report concluded that there is sufficient evidence that the use of ephedrine and/or Ephedra or ephedrine plus caffeine is associated with two to three times the risk of nausea, vomiting, psychiatric symptoms such as anxiety and change in mood, autonomic hyperactivity and palpitations. It was not possible to determine the contribution of caffeine to these events. There were no reports of serious adverse events in the controlled trials.²⁵

From the adverse events reported by one manufacturer of Ephedra-containing dietary supplements and to the FDA, the RAND Report identified what it termed to be ‘sentinel events’. Classification of a sentinel event does not mean to imply a proven cause and effect relationship. These included two deaths, three myocardial infarctions, nine strokes, three seizures and five psychiatric cases associated with prior Ephedra consumption. The report also identified 43 additional cases as possible sentinel events and noted that about half of all the sentinel events occurred in people aged 30 years or younger.²⁵ Hepatotoxicity has also been linked to the use of Ephedra both in traditional Chinese formulations and in weight loss supplements.26–28

Animal exposure to pyrrolizidine alkaloids (PAs), found in several medicinal plants, has led to a dose-dependent swelling of hepatocytes and haemorrhagic necrosis of perivenular cells of the liver, with concomitant loss of sinusoidal lining cells, with sinusoids filled with cellular debris, hepatocyte organelles and red blood cells. These are all features of veno-occlusive disease.²⁹ These effects do not represent an IDR, but rather follow from the direct hepatotoxic activity of these alkaloids. The LD₅₀ for a pyrrolizidine-rich extract of Senecio was found to be 160 mg/kg.³⁰ Despite their similarity in structure, PAs differ in their individual LD₅₀ values and in the organs in which toxicity is expressed. In one study of four PAs, the proportion of the PA removed by liver cultures varied considerably due to differences in the production of reactive metabolites (dehydroalkaloids), which appear to be largely responsible for the toxicity of PAs, and in their conversion to a safer form (GSDHP).³¹ Among pyrrolizidine-containing plants, heliotrope³² and Senecio³³ have been found to be responsible for veno-occlusive disease in humans. Clinical manifestations of poisoning in humans include abdominal pain, ascites, hepatomegaly and raised serum transaminase levels. Prognosis is often poor with death rates of 20% to 30% being reported.³⁴ In vivo studies of coltsfoot, containing senkirkine, have shown some evidence of toxicity.³⁵ However, the key reported case linked to coltsfoot consumption turned out to be a substitution problem. Tea containing peppermint, and what the mother thought was coltsfoot (Tussilago farfara), was associated with veno-occlusive liver disease in an 18-month-old boy. Pharmacological analysis of the tea compounds revealed high amounts of PAs, mainly seneciphylline and the corresponding N-oxide. It was calculated that the child had consumed at least 60 mg/kg body weight per day of the toxic pyrrolizidine alkaloid mixture over 15 months. Macroscopic and microscopic analysis of the leaf material indicated that Adenostyles allariae had been erroneously gathered by the parents in place of coltsfoot. The child was given conservative treatment only and recovered completely within 2 months.³⁶

A review of 18 case reports of pennyroyal ingestion documented moderate to severe toxicity in patients who had been exposed to at least 10 mL of pennyroyal oil. In one fatal case, postmortem examination of a serum sample obtained 72 h after the acute ingestion identified 18 ng/mL of pulegone and 1 ng/mL of menthofuran.³⁷ In another case of ingestion of 30 mL of pennyroyal oil by a pregnant woman, symptoms included abdominal spasm, nausea, vomiting, alternating lethargy and agitated behaviour. Kidney failure and a solid liver necrosis developed subsequently and death occurred 7 days later. In two similar cases where doses used were 10 mL and 15 mL of oil, vomiting, agitation, fainting, flank pain and dermatitis occurred, but with no lasting toxic symptoms.³⁸

Maternal ingestion of blue cohosh (Caulophyllum thalictroides) in late pregnancy has been associated with four documented cases of perinatal adverse events. The first case occurred after a normal labour, where a female infant was not able to breathe spontaneously and sustained central nervous system (CNS) hypoxic-ischaemic damage. A midwife had attempted induction of labour using a combination of blue cohosh and black cohosh given orally (dosage undefined) at around 42 weeks’ gestation.³⁹

In the second case, severe congestive heart failure and myocardial infarction in a newborn male were attributed to maternal consumption of blue cohosh tablets. The woman had been advised to take 1 tablet per day (herb quantity not specified) but she took 3 tablets per day for 3 weeks prior to delivery. Cardiomegaly and mildly reduced left ventricular function were still evident at 2 years of age.⁴⁰ The tablets were not analysed for their content. Stroke in an infant was reported as a possible association with a blue cohosh-containing dietary supplement in the FDA’s Special Nutritionals Adverse Event Monitoring System database (which listed adverse events but was not subject to preconditions, analysis or peer review).⁴¹ The level of documentation of this case is poor.

Finally, a case report linked stroke in a baby with blue cohosh consumption by the mother.⁴² A female infant weighing 3.86 kg was born at just over 40 weeks’ gestation to a healthy 24-year-old woman. The obstetrician reportedly had advised the woman to drink a tea made from blue cohosh because induction of labour was a recognised effect of this herb. A caesarean section was performed after a failed attempt at vaginal delivery. The infant had focal motor seizures of the right arm, which began at 26 h of age, and were controlled with phenobarbital and phenytoin. A computed tomographic (CT) scan obtained when the infant was 2 days of age showed an evolving infarct in the distribution of the left middle cerebral artery. There were no other apparent causes for the baby’s condition.

In a curious development with this fourth case, urine and meconium were positive for the cocaine metabolite benzoylecgonine, and testing of the mother’s bottle of blue cohosh and another brand of the same herb were also positive for this metabolite. Maternal cocaine is a well-known cause of perinatal stroke. Later the authors commented that the finding of a cocaine metabolite in blue cohosh should be interpreted with caution.⁴³ The finding is most likely due to a false positive reading from the analytical tests used (which did not have a high degree of specificity). In other words, blue cohosh most likely contains a phytochemical which reacts like the cocaine metabolite in terms of the test used, but is not related in any way to cocaine.

Adverse effects have also been documented for a pregnant woman ingesting blue cohosh. Nicotinic toxicity was reported following the attempted use of blue cohosh as an abortifacient.⁴⁴ A 21-year-old woman developed tachycardia, sweating, abdominal pain, vomiting and muscle weakness following the ingestion of a blue cohosh tincture. The authors suggested that these symptoms were consistent with nicotinic toxicity and probably resulted from N-methylcytisine, a phytochemical component of blue cohosh. Symptoms resolved over 24 h.

Many plants are designated as poisonous, based on toxic effects either after human exposure or following grazing in livestock. Several commonly and safely used medicinal plants are responsible for toxic effects in livestock, notably St John’s wort and Tribulus. However, the issue here is the amount ingested by the animals, which can be several orders of magnitude greater than the human therapeutic dose. Other factors can also influence toxic effects in ruminants. In the case of Tribulus, rumen bacteria apparently metabolise the steroidal saponins into toxic components. This is not relevant to human metabolism. (See the Tribulus monograph for a full discussion of this phenomenon.)

In general, plants have considerably less acute toxicity than many other agents in our modern environment, such as chemicals and drugs. This could be expected since the chemicals in plants are diluted by a large percentage of inert plant material. This assertion is borne out by statistics, for example data from the American Association of Poison Control Centres (AAPCC). In a recent publication, information from the 1983 to 2009 annual reports of the AAPCC was analysed, together with queries of the 2000 to 2009 AAPCC Toxic Exposure Surveillance System and the National Poison Data System databases.⁴⁵ During 2000 to 2009, 668 111 plant ingestion exposures were reported, with around 90% of these involving single plants. There was a steady decline in the number of plant exposures, falling from 8.9% of all reported exposures in 1983, to 2.4% in 2009. Young children accounted for more than 80% of plant ingestion exposures. Only 45 fatalities were recorded between 1983 and 2009, with Datura and Cicuta species accounting for about one-third of these. The authors concluded that, while plant ingestion remains a common call for poison information centres, morbidity and mortality associated with these were very low relative to the total number of reported plant exposures.

Given the existence of toxic plants, it is accepted by all involved that not all plants are safe to use as remedies. The incidence of these clearly varies from country to country. Appendix B provides a list of several potentially toxic medicinal herbs. With a few exceptions, their use is best avoided, especially during pregnancy and lactation. The individual herb monographs in this book contain detailed toxicity information, where available.

Understanding the key safety issues and demonstrating the safe use of herbal therapy is probably the biggest challenge that faces the future widespread use of medicinal plants. A key issue is that the safety of any given therapy can never be considered in isolation from its efficacy. In every therapeutic task, risks must be weighed against benefits for each particular clinical situation. Therapy is justified only if the possible benefits outweigh the potential risks in an informed risk-benefit analysis. This decision is dependent on an adequate clinical knowledge of the patient and his or her disease, and knowledge of the treatment pertinent to the specific situation.

Although the term ‘benefit-risk ratio’ is convenient and often used, such an assessment is qualitative not quantitative (in other words, the division of a number for risk by a number for efficacy is rarely actually performed) and hence always involves some element of subjectivity. For a drug that is lifesaving, a greater safety risk is acceptable when it is used in that context. This is the reason dangerous therapeutic drugs are tolerated by the regulators.

A major problem in the assessment of many herbs is the lack of hard data supporting their efficacy. Hence, in the eyes of the authorities the benefit is zero, so any risk is unacceptable, as was the case with kava (despite the clinical data). One positive development in this area would be the acceptance of well-established traditional (historical) use as evidence for efficacy. Nonetheless, the fact remains that, in order to preserve the status of herbs, information about efficacy as well as safety is required.

Patients can sometimes experience a mild adverse effect that they attribute to the herbal treatment. Often this is not the case and dechallenge and rechallenge can clarify this. In highly sensitive patients, it can be best to start with a lower dose and build up. The vast majority of clinical trials (see the many examples in the herb monographs) have demonstrated that the side effect profile of a herbal treatment is about the same as placebo.

A number of milder adverse reactions are predictable on the basis of the known phytochemistry of the herb. More details of such side effects are provided in Chapter 2, but a few key examples follow:

Many other potential side effects have been identified for individual herbs and these are outlined in the monograph section of this text.

In general, allergic reactions to herbs are relatively uncommon. A typical allergic reaction, if one occurs, is contact sensitivity. This is acquired only when contact is made with the plant via the skin or mucous membranes. Most herbs have the potential to cause contact sensitivity; however, herbs that contain either resins or sesquiterpene lactones are more likely to have this property. Contact sensitivity can be manifest on the skin either after topical application or in the oral cavity after contact, such as for a gargle or just ingesting a liquid preparation.

Allergic contact dermatitis due to the presence of sesquiterpene lactones (SLs) occurs for many plant species, especially the Asteraceae or daisy family (Compositae). (Note for readers with a chemistry background: in this plant family, the presence of an alpha-methylene on the lactone group is mainly responsible for allergenicity.) It is often observed that individuals who are SL-sensitive tend to develop cross-reactions when encountering other SL-containing species. Commonly used medicinal plants containing SLs include Arnica, feverfew, globe artichoke, elecampane (Inula helenium) and dandelion.

Some other herbs which can commonly cause contact sensitivity include myrrh (Commiphora), cinnamon (Cinnamomum spp), lime flowers (Tilia), propolis (not strictly a herb) and balm of Gilead (Populus candicans).

Anaphylactic reactions can also occur; however, these are quite rare. The Compositae plants are again often involved and the issues for Echinacea and chamomile are fully discussed in their relevant monographs.

Idiosyncratic reactions are reactions that are peculiar to a single individual or a very small group of people. They are by nature unexpected and unpredictable.

In such cases, unless the herbal formula is rechallenged, it is difficult to be entirely sure that the therapy was the cause. However, when the side effects cause considerable discomfort it may be unethical to rechallenge and in many cases the patient is unwilling to try the same formula again.

We cannot rule out the possibility that many so-called idiosyncratic reactions to herbs could be coincidence or a placebo (or in fact nocebo, which is the opposite of placebo, see later) effect. On the other hand, there are some patients (although they are rare) who appear to react to almost anything. This hyper-reactivity is part of their being unwell and will be revealed during the initial case history taking. For example, if a patient reports a history of ‘unusual reactions to drugs’ or ‘being very sensitive to drugs’ it is prudent to take note of this information and make the assumption that, in this particular patient, a reaction to herbal therapy might also occur.

As a general rule, clinicians need to take great care in treating such patients. This is also true for patients who report multiple food sensitivities. When writing a herbal prescription for such patients, it is probably wise to err on the side of caution and use fewer rather than more herbs. This way, if any type of reaction does occur, it may be easier to isolate the cause. In extreme cases, the practitioner may choose to use just one or two herbs initially and add others as the treatment progresses.

Some specific organ toxicities that occasionally seem to occur in herbal therapy may be idiosyncratic reactions. This especially applies in the case of hepatotoxicity (see above). That is, the particular herb does not contain hepatotoxins, but immunologically driven liver destruction is driven by consistent exposure to that herb.

It is a general principle that one should refrain from giving medicines to a pregnant woman unless clearly necessary. Although some herbs have been used safely by women when pregnant and may thus be seen to have a degree of positive vetting, they should be prescribed particularly carefully in the crucial first trimester when fetal organ development is underway. Although there are very few accounts that link any pregnancy problems to herb consumption, too little is known for any sweeping recommendation. Particular caution should be exercised for plants with alkaloidal principles, strong volatile constituents (notably including pure essential oils and plants with high levels of thujone) and in cases where there is a history of miscarriage or where low back or abdominal pains occur. Toxic herbs should be avoided; see Appendix B for such a list.

A number of other herbs should be particularly avoided in pregnancy. In many popular herb books, the term ‘emmenagogue’ is used to refer to a gynaecological remedy. Probably the most frequent indication for such remedies in earlier times was to bring on delayed menstruation; in other words, many ‘emmenagogues’ were used for birth control, as abortifacients. This was likely to be one of the specialist skills of ‘wise women’ and, theoretically, remedies affecting the gravid uterus are as likely to harm fetal growth as to abort pregnancy.

The pregnancy safety ratings advocated in The Essential Guide to Herbal Safety¹ have been adopted for the monographs in this text. This categorisation is designed to remove the subjectivity from assessing the safety information for herbs during pregnancy. The ratings are self-explanatory, but a further discussion is provided in Chapter 10 (How to use the monographs). However, some herbal clinicians might prefer a simpler approach of a list of contraindications and cautions, and this is provided in Table 5.1 for more than just the 50 herbs detailed in this book.

In regulatory terms, the caution referred to above in the case of pregnancy is also extended to the stage of lactation. Although critical organ development is not threatened, there remains some doubt in many cases about how secondary plant metabolites, many of which pass easily and even preferentially into breast milk, affect the baby. Practitioners should therefore maintain a degree of caution in attending to clinical problems affecting mother and suckling baby. However, it should be pointed out that documented adverse effects for herbs used during lactation are minimal, other than milk reduction or reduced infant feeding. Table 5.2 provides some basic guidelines for commonly used herbs.

The issue of adverse herb-drug interactions (HDIs) is probably the most contentious problem in the understanding of the safe use of medicinal plants. Many texts carry pages and pages of theoretically possible interactions for each herb, often based on unsupported extrapolations from pharmacological data (typically in vitro studies). Such information is not only needlessly cautious it is potentially alarmist. The reader might experience such difficulty managing the complexity of the provided information that he or she might conclude that the only safe option is never to recommend any herbs in conjunction with conventional drugs. In addition to these hypercautions, there is also considerable misinformation in the field. For a full discussion of these issues, the reader is referred to the relevant chapter in The Essential Guide to Herbal Safety.¹

While adverse HDIs can certainly be theorised, clinically relevant examples that can be predicted on theoretical grounds are probably uncommon. One such example is the combination of licorice (Glycyrrhiza glabra, G. uralensis) with thiazide diuretics. Prolonged use of both could accelerate potassium depletion. If the patient was also taking digoxin, then a further adverse interaction could occur, since the toxicity of digitalis glycosides is increased by potassium depletion. However, most important adverse HDIs are likely to be unexpected, with case reports representing the best way to discover them.