No.

22 October 2001

Safety Issues in Herbal Medicine: Adulteration, Adverse Reactions

and Organ Toxicities
by Kerry Bone

Adverse Reactions yarrow (Achillea millefolium). Thujone-containing

herbs can also cause headaches.
The potential for an herbal product to cause adverse
Garlic and other sulfur-containing plants, such as the
reactions can be assessed either from the perspective of Brassicas (cabbage family) can inhibit thyroid function.
the phytochemical content of the plant or from published Patients with low thyroid activity should not receive
case reports. garlic in high doses for prolonged periods.2

Bladderwrack (Fucus vesiculosus) and kelp (Laminaria)
A Phytochemical Perspective are rich in iodine which may aggravate or induce
hyperthyroidism when given in high doses for
Common examples of where the known phytochemicals in prolonged periods. Hyperthyroidism in turn can
an herb can impact on its adverse reaction profile are as aggravate osteoporosis.
follows:
Laxative herbs containing anthraquinones (such as

Tannin-containing herbs, e.g. cranesbill (Geranium senna) can cause griping. Abuse can lead to
maculatum) and oak bark (Quercus robur) can inhibit electrolyte loss, especially potassium. Chronic use
trace element and B vitamin absorption. They should leads to a characteristic pigmentation of the colonic
therefore not be used in high doses for long periods.1 mucosa known as “melanosis coli”. This is harmless

Saponins are gastric irritants. Hence, doses of herbs and reversible. Chronic laxative abuse of any kind can
which contain saponins, e.g. horsechestnut (Aesculus damage the colon.3
hippocastanum) and Gymnema (Gymnema sylvestre),
can cause reflux and/or vomiting in sensitive
individuals. The alternative is to give them in enteric-
Individual Herbs
coated tablets or with meals. Some published adverse reactions to commonly used

Pungent herbs such as capsicum and ginger (Zingiber herbs are described below. Due to space limitations, this
officinale) create a burning sensation which patients information is not comprehensive, but does cover most of
may find uncomfortable and may lead to the commonly reported adverse reactions for the herbs
gastroesophageal reflux. In the case of herbs that chosen.
contain mustard oils such as horseradish (Armoracia
rusticana), the burning sensation is real and can cause Ephedra (Ephedra sinensis)
considerable gastric discomfort. High doses of ginger
can cause heartburn. Between December 1993 and September 1995, the

Bitter herbs in high doses may cause some patients to Bureau of Food and Drug Safety, Texas Department of
vomit when given in liquid form due to their strong Health, received approximately 500 reports of adverse
taste. events in persons who consumed products containing

Echinacea and prickly ash (Zanthoxylum clava-herculis) ephedrine and associated alkaloids.4 The FDA received
contain alkylamides which in liquid form cause tingling approximately 800 medical and psychiatric complications
in the mouth and promotion of saliva. In a few directly linked to Ephedra (Ma-huang) and 34 notices of
patients this can result in a choking sensation and deaths between 1993 and 1997.5 However, for many of
perhaps a panic reaction. these deaths the association with intake of ephedrine-type

Thujone can cause CNS stimulation and possibly alkaloids has been challenged.6
epilepsy. Care should be exercised when giving
thujone-containing herbs in high doses to epileptics. Because of the way Ephedra products are marketed i.e. for
These herbs include Thuja (Thuja occidentalis), sage weight loss, for increased energy, heightened sexual
(Salvia officinalis), tansy (Tanacetum vulgare), sensations and as ‘herbal highs’, it is not hard to imagine
wormwood (Artemisia absinthium) and some types of that exceeding the recommended dosage might not be an

Not for Public Distribution. For Education of Health Care Professionals Only. 1
uncommon occurrence. For example, one product label following an error of judgment in his work as a
stated “acts on the same basis as ‘ecstasy’, triggering technician. At admission he revealed a 3-month
similar but not identical physical reactions in the body”. history of depression, feeling overwhelmed, poor
These claims are outside the traditional uses of Ephedra, concentration, “thinking too many thoughts at once”,
where it is primarily used for asthma and respiratory irritability, guilt and suicidal thoughts. He also
diseases. experienced episodes of “euphoria” lasting for up to 3
days. Over the next 5 months he was trialled on
However, there are reports of adverse reactions attributed several antidepressants for 2-3 weeks each but
to ephedrine and Ephedra-containing products which were discontinued them all because of increased irritability
taken at the recommended dose.4,7 or sedation.

A 35-year-old woman was diagnosed with acute His symptoms persisted and when questioned more
myocardial infarction, secondary to cardiac spasm, closely he admitted to taking Ephedra regularly over
after taking an ephedrine-containing supplement for the last 2 years to help with workout performance. On
weight loss. She had taken the supplement for 30 giving up the herb his moods returned to normal and
days at the recommended dosage and had stopped for he resumed full duty without further psychiatric
1 week while on vacation. The attack occurred 1-2 intervention.5
days after recommencing the supplement. Since
discontinuing the product she has had no further Ginkgo (Ginkgo biloba)
cardiac-related symptoms.
Ginkgo is a very widely used herb and is popular for the
treatment of cerebral insufficiency and dementia. To give

Three weeks after beginning daily use of a dietary
an indication of its popularity, in 1989 it was the most
supplement containing ephedrine a 44-year-old man,
prescribed medicine in West Germany, where more than 5
with no known cardiovascular risk factors, died from
million prescriptions were written.9
acute coronary artery thrombosis. He was given the
supplement by his family physician as a substitute for
Spontaneous Hematomas
his daily coffee and cocoa.
There have been a few reports of spontaneous hematomas

Seizures were experienced by a 38-year-old woman occurring in patients taking Ginkgo, however, spontaneous
after she took 4 tablets of an ephedrine-containing bleeds, especially in the brain, are not an uncommon
dietary supplement (2 tablets initially and another event in the older population. Considering the widespread
2 tablets 5 hours later as recommended on the label). use of Ginkgo, particularly in elderly people, there is some
She had no history of seizures and was taking no other doubt that Ginkgo was responsible.
medication other than the contraceptive pill. At one
stage she was hospitalized and treated with
A 33-year-old woman started experiencing headaches,
antiseizure medication. It is unclear whether or not which increased in severity over a 3-month period
this medication was continued. She experienced no with accompanying diplopia, nausea, and vomiting for
seizures after discontinuing the dietary supplement. two weeks. She had no significant medical history. Her
doctor prescribed ergotamine/caffeine tablets. An MRI

A 39-year-old male who was taking pravastatin for revealed bilateral subdural hematomas. She
hypercholesterolemia and furosemide for underwent evacuation of the hematomas and her
hypertension developed hypersensitivity myocarditis headaches improved significantly but a mild chronic
after taking Ma-huang (1-3 tablets twice daily) for 3 headache remained.
months, along with other vitamin supplements. He
received medical treatment and 2 months later at a Three months later it was discovered that she had
follow-up examination had no signs of myocarditis. been taking Ginkgo, 60 mg twice a day for 2 years.
The only other medications she took prior to the

A letter published in the BMJ in September 1996 diagnosis of hematomas were acetaminophen
reported the case of a 34-year-old man suffering from (paracetamol) and ergotamine/caffeine tablets. She
psychosis after taking Ephedra (dose not stated) over did not take aspirin or other NSAIDs.
the previous 10 days. He had no history of mental
illness and his symptoms resolved quickly once he Upon examination at this time her neurologic
stopped taking Ephedra. No treatment was given and examination was normal, MRI showed only
follow-up confirmed that he remained free of postoperative changes, there was no reaccumulation
symptoms.8 of subdural fluid. Complete blood count, liver and
kidney function tests, prothrombin time and partial

A US Marine sergeant (27-year-old male) was taken to thromboplastin time were all normal. Her bleeding
an emergency centre after threatening suicide
Not for Public Distribution. For Education of Health Care Professionals Only. 2
 times were prolonged at 15 minutes and 9.5 minutes, Ginseng (Panax ginseng)
with normal range being 3 minutes to 9 minutes.
There are many different ‘ginsengs’ used in herbal
medicine around the world and product labels do not
She was advised to discontinue the Ginkgo and was
always differentiate the species, simply referring to the
re-examined 35 days later. Bleeding times were 6.5
contents as ‘ginseng’. When reports occur these products
minutes and 6.5 minutes. On follow-up 15 months
are often not analyzed. Therefore it can be difficult to
later she had experienced no further headaches or
assess the validity of reports associated with ginseng.
other neurologic symptoms. She no longer takes
Ginkgo biloba.10
Stevens-Johnson Syndrome

In another case, a 72-year-old woman complaining of
A 27-year-old student from China, who was a regular
memory impairment and dizziness was found to have ginseng user, developed a sore throat and was
a small frontal subdural hematoma that was possibly prescribed aspirin (dose not stated) and local
several months old. She had been using Ginkgo, antibiotics for 4 days. Three days later he started
50 mg three times a day for 6–7 months. There had taking ginseng, two pills/day (dose not stated) for 3
been no history of head trauma.11 days, to help with exam preparation. He then
developed conjunctivitis, dry cough, and a rash on his

A third case was reported in 1998 in which a 61-year- face. Hospital admission occurred 3 days later by
old man presented with a 5-day history of headache, which time his symptoms had progressed to include
back pain, nausea, and sleepiness. On examination, no erosions of the mouth and urogenital mucosa as well
physical abnormalities were found, including as corneal ulceration, a presentation typical for
neurological status. Blood pressure, blood analysis, Stevens-Johnson Syndrome (SJS).15
prothrombin and partial thromboplastin times were all
normal. His bleeding time was elevated to 6 minutes Controversially, the authors concluded that the ginseng
(normal 1-3) and he was subsequently diagnosed with was the most likely cause. However, having not tested the
a subarachnoid hemorrhage. He had been taking herbal tablets they concede that the ginseng may have
Ginkgo, 40 mg tablets 3 to 4 per day for 6 months been adulterated with corticosteroids. It is worth noting
prior to the onset of his symptoms. He stopped the that several drugs including NSAIDs and corticosteroids
Ginkgo and 4 months later his bleeding time was 3 have been shown to be associated with SJS.
minutes.12
Cerebral Arteritis

A case of parietal hemorrhage was recently reported

In another report a 28-year-old woman developed
in association with no previous medical or drug
cerebral arteritis after ingesting approximately 200 mL
history, other than use of Ginkgo in the preceding 18
of extract made with approximately 25 g of dried
months.13
ginseng root brewed in rice wine. Two hours before
taking the ginseng she had taken 500 mg of
It is interesting to note the results of a placebo-controlled
paracetamol for a sore throat. She developed an
randomized trial of Ginkgo extract for the treatment of
explosive headache, nausea and vomiting, and chest
dementia. Three hundred and nine patients took part in
tightness eight hours after taking the ginseng extract.
the trial and during its course one subdural hematoma
She took more paracetamol (within recommended
occurred, however it did not occur in the Ginkgo treated
dosage range), which relieved the headache
group – it occurred in the placebo group.14
temporarily. She was hospitalized 6 days later and the
headache gradually subsided over the next 10 days.
Rowin and co-workers, the authors of the case report on
the 33-year-old woman with bilateral hematomas,
Cocaine and amphetamines are known to induce a
commented on reports involving Ginkgo, including possible
similar clinical picture, however these causes were
drug interactions in a letter to the journal Neurology. They
ruled out. The acetaminophen (paracetamol) was also
concluded that there was no proof that Ginkgo contributed
ruled out as a cause. Although it was acknowledged
to the hemorrhages in these patients, or even that there is
that ginsenosides do not have an amphetamine-like
any clinically relevant antiplatelet effect of this
vascular effect and are chemically different from
medication. But perhaps paradoxically they also state until
amphetamines, the authors suggested it was most
there is evidence to the contrary, it seems prudent to be
likely that the cerebral arteritis was related to the
judicious in the use of Ginkgo, and to instruct patients who
ingestion of a large amount of ginseng extract.16
are taking anticoagulants not to use this herbal medicine.14
Estrogenic Effects

A 70-year-old woman developed swollen, tender
breasts with diffuse nodularity after taking ginseng
Not for Public Distribution. For Education of Health Care Professionals Only. 3
 powder (dose not stated) for 3 weeks. Her symptoms unlikely to occur with normal therapeutic doses.20 (See
abated when the ginseng was stopped. The ginseng also later in this article for potential hepatotoxic effects
was rechallenged twice and the same breast effects from kava).
occurred. Prolactin levels were not effected by the
ginseng powder. She did however, report a general St John’s Wort (Hypericum perforatum)
feeling of “well being” while taking ginseng.17
Although there have been recent, unexpected reports
(January 2000) of herb-drug interactions involving St John’s

A 48-year-old woman was admitted to hospital with a
wort (see later) there are, despite its extensive use, very
three-week history of metrorrhagia. She had never
few reports of adverse reactions. Its use continues to grow
experienced menstrual disorders before. On
and it is often the medicine of choice for the treatment of
questioning it was discovered that she had been
depression because of its efficacy and low incidence of
taking a ginseng product for 2 months. The
side effects when compared to conventional
metrorrhagia disappeared 4 days after discontinuing
antidepressant pharmaceuticals. It has become a
the ginseng.18
mainstream medicine in Germany for the treatment of
depression with 20 times more prescriptions written for St
Kava (Piper methysticum)
John’s wort than for Prozac.21 In Europe in 1998 the total
In 1995 neurologists in Germany19 reported on four sales figures for St John’s wort were quoted as US$6 billion
patients who presented with symptoms suggestive of (probably an overestimate).22 Sales in the United States
central dopaminergic antagonism after using various kava amount to $200 million a year.23 Sales of St John’s wort
preparations. reportedly increased by 2,800% in the USA in one year.22

Patient 1, a 28-year-old man, with a history of Over a 30-year period (1968 to 1998) the World Health
treatment for anxiety, experienced involuntary neck Organization’s Collaborating Center for International Drug
extension with forceful upward deviation of his eyes Monitoring received 57 reports of possible adverse
90 minutes after taking the first dose of a kava reactions relating to monopreparations of St John’s wort
product (100 mg extract). The symptoms subsided from Sweden, Ireland, Germany and Bulgaria. Forty-nine
within 40 minutes. reports for multi-ingredient products containing St John’s
wort were also received.

Patient 2, a 22-year-old woman, took kava for the
treatment of anxiety and nervousness. Four hours Data obtained from the national drug safety bodies in
after taking the first morning dose she experienced Germany and the United Kingdom, covering a period 1989
involuntary oral and lingual dyskinesia, tonic rotation to 1997, revealed that 2 cases were reported in Germany
of the head, and painful twisting movements of the for oral administration of multi-ingredient products. In one
trunk. She was treated with biperiden (an case a pustular rash occurred, and in the other nausea,
anticholinergic drug used in the treatment of nervousness, increased sweating, weight loss and
Parkinson’s disease) and her symptoms immediately anorexia. In the second case the patient was also taking an
subsided. appetite suppressant and antidepressant medication
(MAOI). No reports were received by the UK body during

The third patient was a 63-year-old woman who this time.
experienced similar symptoms after taking 150 mg
kava extract three times a day for four days. She was Photosensitivity
also treated with biperiden and immediately the
The results of a placebo-controlled randomized clinical trial
dyskinesia stopped.
to evaluate the increase in photosensitivity in humans
after taking high dose St John’s wort extracts was

In the fourth case, a 76-year-old woman being treated
published in September 1997.24 The fifty volunteers
for Parkinson’s disease reported a worsening of her
received 600 mg of St John’s wort extract 3 times a day
Parkinson’s symptoms after taking 150 mg kava
(5.6 mg/day total hypericins). Comparison of UVA light
extract (prescribed by her general practitioner) twice a
sensitivity before dosing, with day 15 of treatment,
day for 10 days. She returned to baseline within two
showed a slightly increased sensitivity. This increase in
days of stopping the kava.
cutaneous light sensitivity could be compensated by
reducing irradiation time by 21%. There was no significant
In view of these cases it would be prudent not to prescribe
change in sensitivity to UVB. This study indicates that
kava to patients who have conditions characterized by low
normal use of St John’s wort is unlikely to result in
dopamine such as Parkinson’s Disease.
photosensitivity, although excessive skin sensitivity or
massive light exposure could result in rare reactions.
There are also reports of a skin rash occurring due to
chronic, excessive use of kava. ‘Kava dermopathy’ is very

Not for Public Distribution. For Education of Health Care Professionals Only. 4
Mania manufacturer). She had been taking it for 1½ years,
including the 9 months of pregnancy and 2 weeks of
Antidepressants are known to precipitate mania or cause
breastfeeding. No other medications were being
rapid cycling between depression and mania. They may
taken.
also contribute paradoxically, to treatment-resistant
bipolar depression. Four cases of mania associated with
She had noticed increased and thicker hair growth on
the use of St John’s wort have been reported. In the two
her head, face and pubic area and had experienced
cases23 discussed below the dose of St John’s wort taken
repeated premature uterine contractions during late
by the patients was 900 mg of standardized extract daily.
pregnancy. When her son was born he had thick black
pubic hair, hair over the entire forehead, and swollen,

In the first case, a 20-year-old college student who
red nipples. She was advised to cease breast feeding
felt depressed and irritable presented to a psychiatric
at 2 weeks because of excessive weight gain by the
care unit. His history revealed a previous episode
infant. His excessive body hair began to fall out at 2
consistent with mania (for which he was not treated)
weeks and was scant at 7½ weeks. The herb was not
and an uncle with a history of bipolar disorder. He was
analyzed at this time.25
diagnosed with having symptoms consistent with a
major depressive episode of bipolar disorder. Rather
As a result of this report a researcher at the Bureau of Drug
than take the recommended treatment immediately
Research, Canada, collected three samples of Siberian
he opted to try St John’s wort.
ginseng powder from the manufacturer who produced the
tablets that the woman had taken. A number of tests
After taking the St John’s wort for 3 days he
revealed the material was in fact not Siberian ginseng, but
developed extreme agitation, irritability, pacing,
probably Periploca sepium (Chinese silk vine).26
anxiety and uncharacteristic, irrational behavior. St
John’s wort was discontinued and drug treatment was
Subsequent research on a powder labelled as Siberian
instigated. Two weeks later his condition had
ginseng and obtained from the same manufacturer, also
normalized.
identified as Periploca sepium, demonstrated no
androgenicity on oral administration to rats. So, the

The second case is that of a 51-year-old woman with a
mystery remains. However, we can be sure that Siberian
history of mania. She had been treated with lithium
ginseng was not involved.27
and haloperidol for 15 years but for the last 10 years
had remained symptom free without any medication.
She started to take St John’s wort because she felt Specific Tissue Toxicity
stressed and depressed. She had no symptoms of
major depression. Within a few days she began to
Hepatotoxicity
exhibit “bizarre” behavior, disorganized speech and Sporadic reports have appeared in the literature linking
experienced hallucinations. Lithium and haloperidol hepatotoxicity to the use of both western and Chinese
were started and her symptoms improved within 2 herbs. While in some cases this has been clearly linked to
days. specific herbs such as greater celandine (Chelidonium
majus) and germander (Teucrium chamaedrys), one study
In view of these reports, it would be wise to use St John’s on traditional Chinese herbal medicine found no single
wort cautiously in patients with a history of manic herbal ingredient could account for the observed cases of
episodes. liver injury.28 Since little is known about the frequency of
such effects, a study was initiated in Germany to
Siberian Ginseng (Eleutherococcus senticosus) investigate this phenomenon in a hospital for traditional
The case listed below is a good example of the importance Chinese medicine.29
of implementing the appropriate measures to ensure the
authenticity of an herb. All 1507 patients admitted for inpatient treatment
between February 1994 and July 1995 were screened for
Neonatal Androgenization blood levels of transaminase enzymes. An elevation of
alanine amino transferase (ALT) above twice the
A report in the early 1990s reporting “maternal use of maximum normal level was taken as indicative of liver
ginseng and neonatal androgenization”, caused much injury and was found in 14 patients. In 13 of these a causal
controversy at the time. relationship with Chinese herb therapy seemed possible. A
relationship was deemed to be likely for only one patient.

The case is that of a 30-year-old woman who had just However, all 14 patients were also taking conventional
had her second child 2 weeks earlier. She had self- drugs. Follow-up values of ALT within 8 weeks after
prescribed Siberian ginseng (650 mg) tablets twice discharge were normal in 11 patients (six of them had
daily (twice the dose recommended by the

Not for Public Distribution. For Education of Health Care Professionals Only. 5
continued with their herbs) and near normal in the Rehmannia glutinosa. The herbal mixture did not
remaining three. contain pyrrolizidine alkaloids or aflatoxins.30

The authors concluded that the data available so far Germander (Teucrium chamaedrys)
suggest that clinically relevant hepatotoxic effects from

Two women developed severe acute hepatocellular
Chinese herbs are relatively rare. In their discussion, the
liver injury within 1 to 2 months of treatment with
authors highlighted that, while in a few published cases
wild germander (Teucrium chamaedrys), for weight
liver enzyme elevations recurred and were even worse
loss. The patients recovered after discontinuing the
after re-exposure to the offending herbs, this was not
herbal preparation. Involuntary rechallenge in one
observed in their study. They suggested that for these
patient resulted in reappearance of symptoms of liver
published cases the responses might have been
injury.31
idiosyncratic and are likely to occur at a lower frequency
than the reactions observed in their study. Further to this,

Reports of 26 cases of cytolytic hepatitis and several
more than 6000 patients have been treated in the German
additional cases (including one case of fatal fulminant
hospital and no serious cases of hepatic injury have been
hepatitis) prompted the French health authorities to
observed.
ban all preparations containing germander in May,
1992.32
Since 5 of the 14 patients had a previous episode of liver
damage (such as hepatitis A), the possibility exists that

In seven patients who developed hepatitis after
this history might increase their susceptibility to elevated
germander consumption, jaundice disappeared within
ALT. Another point worth noting about the study was that
8 weeks of discontinuing the herb and complete
dosages used were relatively high (100–120 g per day by
recovery was achieved in 1.5 to 6 months. In three
decoction).
cases, re-administration of germander resulted in
recurrence of hepatitis.33
Given these high doses compared to western herbal
medicine and the authors’ conclusion that clinically

A 68-year-old woman died from hepatic failure after
significant hepatotoxicity is relatively rare, it would not be
consuming germander tablets for weight loss. (Three
unreasonable to suggest that with a few exceptions such
tablets per day (containing 150 mg germander) for 2
as those mentioned above (and avoiding herbs which are
weeks, and 6 months later at the same dosage for 1
known to be acutely hepatotoxic), idiosyncratic liver
to 2 weeks.)34
damage from western herbs is also likely to be rare.

Species of Teucrium (germander) can be substituted
Documented Cases of Suspected Hepatotoxicity
for skullcap (Scutellaria laterifolia) and this probably
There are a number of cases of liver toxicity reported in explains the cases of hepatotoxicity which appeared to
the literature. The cases listed below involved long-term involve skullcap. Over-the-counter sale of germander
ingestion of herbal medicines and other factors including is not permitted in Australia.
alcohol, drugs, hepatitis of viral or autoimmune origin, and
previous history of biliary disease were ruled out as the Chaparral (Larrea tridentata)
cause of the hepatotoxicity.

A 33-year-old woman developed subacute hepatic
necrosis after several months of ingestion of chaparral

An herbal tranquillizer ostensibly containing skullcap
leaf (Larrea tridentata). Symptoms first appeared 3
(Scutellaria lateriflora), valerian (Valeriana officinalis),
months after she began taking 15 tablets per day
hops (Humulus lupulus) and gentian (Gentiana lutea)
(dose unknown). She reduced the tablets herself to
caused hepatitis (probably caused by germander – see
one tablet per day and her health improved. She then
below).
increased the dose and one month later was admitted
to hospital. The chaparral was discontinued and the

A product ostensibly containing skullcap and broom
patient’s liver recovered.35
(Cytisus scoparius) caused jaundice (probably caused
by germander – see below).

A 60-year-old woman ingested chaparral (together
with garlic powder, nettle and chickweed) for 10

Chinese herbs used for treatment of eczema reputedly
months and developed severe hepatitis which
caused hepatitis on first exposure (taken for 3 to 5
progressed to end-stage liver failure requiring liver
months) and acute liver failure leading to death after
transplantation. Three weeks prior to admission into
the second exposure (taken over 2 to 3 weeks). This
hospital the patient had increased her intake from 1 to
herbal mixture contained Cocculus trilobus, Dictamnus
2 capsules per day to six (dose unknown). Jaundice
dasycarpus, Eurysolen gracilis, Glycyrrhiza spp,
occurred 2 weeks later. The patient was also taking
Lophatherum spp, Paeonia spp, Potentilla spp and
Diltiazem, which was dismissed as a possible cause
Not for Public Distribution. For Education of Health Care Professionals Only. 6
 based on the clinical and histologic presentation. It is cases of hepatitis may be caused by greater celandine
believed that the patient developed subclinical (in Germany, where the herb is more widely used
hepatotoxicity from chronic use of chaparral and when than in other countries).
she increased the dose, acute liver injury was
superimposed on chronic liver disease resulting in The mechanism behind the hepatotoxicity of greater
fulminant hepatic failure.36 celandine remains unclear. An idiosyncratic reaction seems
most likely because there appeared to be no dose

A recent FDA review of 18 case reports concluded that dependency and the period of intake before symptoms
there was evidence of hepatotoxicity in 13 cases. The appeared was long and variable.40,41 Low-grade
predominant pattern of liver injury was categorized as autoimmunity had developed in 8 of 9 tested patients.41
drug-induced cholestatic hepatitis.37
Herbalists treat greater celandine with respect. For
Greater Celandine (Chelidonium majus) example, a recent herbal text suggests that: “High doses
should be restricted to short-term use and long-term use
The potential association of greater celandine
of normal doses is not preferred.” Typically, herbalists
(Chelidonium majus) with hepatotoxicity was first reported
prescribe tincture or fluid extract doses which do not
in the British Medical Journal.38
exceed the equivalent of 1 g per day of dried herb and
they do not prescribe the herb for extended periods.42

A case history was recounted of a 69-year-old woman
who developed symptoms of acute hepatitis after
However, a German clinical trial published in 1993
taking 6 to 15 herbal tablets per day for 6 weeks. The
changed this pattern of use for greater celandine in that
tablets contained horsechestnut leaf, yarrow, greater
country.43 In this trial, 608 patients with cramp-like pains
celandine, sweet clover, milk thistle and dandelion
in the gastrointestinal tract or gall ducts were treated
root. Her prescription medications were thyroxine and
(using an uncontrolled design) over a 3-month period with
ibuprofen. Withdrawal of ibuprofen and the herbs for
a high-dose standardized extract (dried herb equivalent
two weeks returned her liver function to normal
dosage was 3 to 5 g per day). A good response was
levels, but reintroduction of the herbal tablets resulted
observed in 87% of cases. This research led to greater
in a return of her symptoms.
celandine being used over extended treatment periods as
a spasmolytic agent. For example, in one of the hepatitis

In a case study from Germany presented in 1997,
cases the patient had consumed a high dose of greater
hepatotoxicity after ingestion of a preparation of
celandine for the treatment of period pains.40 The long-
greater celandine was described by Greving and co-
term use of greater celandine at high doses as a
workers.39 The same authors went on to publish this
spasmolytic is not consistent with its main traditional use
and an additional case history one year later.40 In both
for gall bladder and liver disease.
cases, patients were taking several capsules per day of
200 mg of dry extract of greater celandine (equivalent
Greater celandine is also used in traditional Chinese
to about 1 g of dried herb and containing about 4 mg
medicine. The dose used in China is 3 to 9 g per day or
of alkaloids).
even higher. However, these doses are generally
administered by decoction and this method may not

In what amounts to convincing evidence of the
efficiently extract the alkaloids.
association of greater celandine intake and acute
hepatitis, a different research team in Germany
Kava (Piper methysticum)
recently described 10 cases accumulated over two
years of observations.41 The course of the hepatitis Reports on liver failure and medical hepatitis after taking
was mild to severe and was associated with five kava led the Swiss-based Interkantonale Kontrollstells (IKS)
different commercial products containing greater to classify its risk level as ‘infrequent, but still to be taken
celandine. Marked bile obstruction was observed in 5 seriously’ (Schweizerische Artztezeitung 2000; 81: 1335-
patients, but liver failure did not occur. Other possible 1336). In all, the IKS is aware of only nine reports on liver
causes of liver disease (viral, autoimmune, hereditary, damage related to kava extract. Symptoms usually
alcohol, and secondary biliary) were excluded by manifest within 3 to 16 weeks after having taken doses
laboratory tests and imaging procedures, and liver equivalent to at least 60 mg daily of kava lactones, but
biopsy specimens were consistent with drug-induced more usually, after having taken 210 mg or more daily.
damage. After discontinuation of greater celandine, Administration of kava preparations should cease
rapid recovery was observed in all patients and liver immediately on presentation of symptoms such as:
enzyme levels returned to normal in 2-6 months. uncharacteristic tiredness; loss of appetite; nausea or
Unintentional rechallenge led to a second flare of jaundice. An immune-allergic mechanism was discussed.
hepatic inflammation in one patient. The authors
suggested that a significant proportion of unexplained

Not for Public Distribution. For Education of Health Care Professionals Only. 7
In the meantime, Krewel Meuselbach, producer of the Akebia extract.50 Two patients in the United States recently
German market leader kava product (Antares 120), reacted were reported to have developed end-stage renal disease
with a press release indicating that the nine cases [cited in association with the use of botanical preparations
by the IKS] concerned only those preparations using kava containing aristolochic acid.50 A number of products
prepared by acetone-based extraction. In contrast, Antares containing Aristolochia have recently been recalled.51
uses ethanol to extract the herb (as do most herbal
companies). Preparations using ethanol processes have a Adulteration and Adverse Reactions
large market share. According to market analysts Manfred
Bonin, a total of 80 million daily doses of Antares were Perhaps the most commonly documented reason for
taken since its introduction in 1992 up to the end of 1999. adverse reactions to herbal products is the presence of
Only one single suspicious case was reported: a patient, adulterants, as has already been described in the case of
who was simultaneously taking another medication, Aristolochia. This adulteration may be due to:
demonstrated elevated aminotransferase – which fell once
Environmental contamination of the herb with a
she stopped taking Antares and rose once she resumed.44 chemical or pathogen.

Unintentional substitution of one or more herbal
Nephrotoxicity ingredients with a toxic species.

Intentional addition of a “natural” active component
In Belgium, a group of medical doctors running a slimming which is responsible for the adverse reaction, such as
program included some herbs in their treatment. One of a microorganism, mineral or nutrient.
the herbs they wished to include was Stephania tetrandra,
Intentional addition of a conventional chemical drug,
but patients in fact received Aristolochia fangchi which either of natural or synthetic origin.
contains aristolochic acid.45,46 This substitution is relatively
common. Many women died from severe kidney damage. These problems can generally be overcome by responsible
It is thought that a diuretic drug, which the women were manufacture, adequate testing and above all a
receiving, potentiated the nephrotoxicity of the aristolochic commitment to pharmaceutical level Good Manufacturing
acid by decreasing acidification (i.e. increasing pH) in renal Practice (GMP). Examples of these four types of
tissue. The drug was acetazolamide, a sulfonamide drug adulteration have appeared in the scientific literature.
which can cause metabolic acidosis, anorexia and weight
loss and can be nephrotoxic. In 1997 it was reported that A report from Taiwan describes a case study of a patient
two women involved in this tragedy have subsequently who developed a unique syndrome of multiple renal
developed urothelial cancer due to the genotoxicity of tubular dysfunction after ingestion of a Chinese herbal
aristolochic acid.47 formula contaminated by cadmium.52 A United States case
report described a bone marrow transplant recipient who
A paper published in June 1999 reports further cases of developed hepatic zygomycosis (a type of fungal infection)
urethral cancer. Cosyns and co-workers tested 10 patients after ingestion of a range of herbal and naturopathic
suffering from Chinese-herb nephropathy (A. fangchi). Four medicines.53 The organism Mucor indicus was isolated from
(40%) were found to have urethral carcinoma, and cellular the patient’s liver aspirate and from one of the medicines
atypia was found in all of the 10 patients.48 – in fact a Lactobacillus preparation, not the herbal
products. A recent US survey found substantial heavy
Nortier and co-workers (June 2000) concluded that the metal contamination in several Asian traditional
incidence of urethral cancer among patients with Chinese- remedies.54
herb nephropathy (CHN) is high and that the risk was
related to the cumulative dose of the herb. They report A letter to the British Medical Journal in 1996 asserted that
treating 105 patients with CHN and 43 of whom have been Podophyllum poisoning has developed into a mini-
admitted with end stage renal failure. Thirty-nine of these epidemic in Hong Kong.55 The poisoning is caused by
patients were tested for urethral carcinoma. Eighteen ingestion of the herb known in Cantonese as gwai-kou,
cases of urothelial carcinoma were found and mild-to- which is derived from the roots and rhizomes of
moderate dysplasia were found in 19 patients. Cases of Podophyllum hexandrum (also known as P. emodi). The
CHN have also been reported in France, Spain, Japan, the herb appeared in Hong Kong in 1989 as an adulterant of
United Kingdom, and Taiwan where cases of urothelial lung-dam-cho (Gentiana spp.) and led to two cases of
carcinoma have also been detected.49 neuropathy and encephalopathy. Around the same period,
this herb was found in Taipei and Kuala Lumpur as an
In 2001 FDA laboratory analyses revealed the presence of adulterant of another herb, wai-ling-sin, which is the root
aristolochic acid in certain botanical products and dietary of Clematis spp. Recently, nine cases of neuropathy have
supplements sold in the United States. Some of the been reported in Hong Kong. About 10% of 234 samples of
products were labeled as Aristolochia (also called Virginia wai-ling-sin taken from Hong Kong outlets were found to
snakeroot) and as botanicals for which it is a likely be Podophyllum.
substitute, e.g. Stephania tetrandra, Clematis armandi, and

Not for Public Distribution. For Education of Health Care Professionals Only. 8
Sometimes unintentional adulteration can occur when However, the need for better gathering of safety data
harvesting an herb from the wild for personal use. is highlighted by some of the current reports.
Venocclusive disease of the liver was diagnosed in an 18-
month-old boy who had regularly consumed an herbal tea
The incidence of adverse reactions to herbal products
mixture.56 The tea contained peppermint and what the appears to be low when compared to conventional
mother thought was coltsfoot (Tussilago farfara). However, medications (although better data are needed for both
macroscopic and microscopic analysis of the leaf material sectors of the market). A useful comparison can be
indicted that alpendost (Adenostyles alliariae) had been made with the adverse reaction profile for non-
erroneously gathered by the parents instead of coltsfoot. selective non-steroidal anti-inflammatory drugs
The two plants can be confused, especially after the (NSAIDs). A study published in the New England
flowering period. This may also explain why coltsfoot has Journal of Medicine in 1999 provided the following
developed a reputation as a toxic herb in some quarters. disturbing facts:59

10 to 20 percent of patients have dyspepsia while
The title of a letter to the Journal of the American Medical taking these NSAID drugs.
Association misleadingly attributes a case of diuretic
13 of every 1000 patients with rheumatoid
resistance to ginseng.57 However, the text of the article arthritis who take NSAIDs for one year have a
clearly states that this acute adverse renal effect was due serious gastrointestinal complication.
to the element germanium, which appears to be present
In 1997 about 16,500 patients in the US died from
in the tablets as a nutritional supplement. The authors the gastrointestinal toxic effects of NSAIDs (which
seemed to be unable to differentiate between herbal and was about the same number of deaths from
mineral components and rather ambiguously refer to a AIDS).
“germanium-containing ginseng preparation” throughout
the text of their letter.
Historical use of an herb cannot be relied upon as an
indicator of safety (hence the urgent need for active
Perhaps the most reprehensible form of adulteration of safety surveillance for herbal products). This is well
herbal products is the intentional addition of a illustrated by the case of Aristolochia. Various species
conventional drug which is not declared on the label. of Aristolochia (which all contain the toxic aristolochic
Cow’s Head brand tung shueh is a product promoted for acids) were in use in Europe, the US and India in the
problems of the “heart, liver and kidney” as well as other 19th and 20th centuries. Although some
problems such as spasms, rheumatism and poor pharmacopeias did note renal toxicity in animal
circulation. Analysis found 3.86 mg of indomethacin, studies, the capacity of the medicinal species of this
16 mg of mefenamic acid, 7.94 mg of diclofenac and genus to cause renal damage and cancer in humans is
0.73 mg of diazepam per pill.58 At the recommended dose not mentioned.
of 12 pills a day a consumer would unknowingly ingest
10 mg of diazepam and be at risk of side effects from the Acknowledgment
anti-inflammatory agents.
The substantial contribution of Berris Burgoyne in the
Anderson also described jin bu huan anodyne tablets for preparation of this article is gratefully acknowledged.
sale in health food shops in Denver which contained 36%
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1899

This article was originally printed in the Townsend Letter for

Doctors and Patients, #219, October 2001.
See www.tldp.com
Reprinted with permission.

Not for Public Distribution. For Education of Health Care Professionals Only. 10