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Chanetal. Chin Med (2021) 16:61
https://doi.org/10.1186/s13020-021-00472-9
REVIEW
The toxicology anddetoxication
ofAconitum: traditional andmodern views
Yau‑Tuen Chan, Ning Wang* and Yibin Feng*
Abstract
Aconitum carmichaeli Debx.-derived herbal medicine has been used for anti‑inflammation and anti‑arrhythmia
purpose for more than two thousand years. It is processed into Chuanwu (Radix Aconiti praeparata) and Fuzi (Radix
Aconiti lateralis praeparata) in Traditional Chinese Medicine, which are two useful drugs but with toxic properties.
There have been patients poisoned by accidental ingestion of Aconitum plants or misuse of the herbal drug, and this
is of great concern to study in‑depth. In this review, we provided the traditional and contemporary practice of using
Aconitum herbs as medicine, from functions, processing methods to toxicity in ethnomedicine aspects to discuss the
underlying connections of traditional and modern understanding on the toxicity of Aconitum plants. We summarized
the functions and toxicology of the herbal drugs are analyzed from chemical and clinical aspects, with the help of
traditional and modern knowledge of medicine. The medicinal doses and lethal doses determined by researches are
summarized, and the usage and processing methods are updated and reviewed in the modern view. In addition,
clinical management of poisoned cases using western medicine is discussed. This review provides insights and aware‑
ness of safety when using Aconitum‑derived herbal medicine, and the application of modern scientific knowledge to
optimize the detoxification processes. We suggest the possibility to renew the current standard processing method
from the official Pharmacopoeia all over the world.
Keywords: Aconitum, Aconitine, Toxicology, Drug processing, Detoxification
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Introduction
Aconitum is a genus of herbal medicine in the Ranunc-
ulaceae family, with more than 400 species all over the
world [1]. Aconitum plants, also having the names of
aconite, monkshood, wolf’s bane, queen of poisons, are
a branch of herbal drugs in traditional Chinese Medicine
[2]. Caowu, Chuanwu, Fuzi and Tianxiong are four exam-
ples of Chinese herbal drugs that are deriving from the
same species Aconitum carmichaelii Debx., which is the
common herb to be used nowadays [3]. e medical use
of Aconitums, regardless of the raw or processed herbs,
are highly cautious since its obvious toxicity. Despite the
potential danger, the clinical applications of Aconitum
species are becoming more systematic with the increas-
ing understanding of its toxicology and methods of
detoxifications.
ere have been poisoned cases reported even until
recent years in herbal medicines used regions, including
China, Hong Kong [4], Taiwan and India [5], etc. It may
sound dangerous to use these kinds of toxic drugs. How-
ever, due to the essential role of the Aconitum in many
diseases, including rheumatism, joint pains [6], oedema,
gastroenteritis [7], asthma, abdominal pains [8, 9], and
some gynaecological disorders like irregular menstrua-
tion and dysmenorrhea, it is a very efficient herbal drug
to ease pains, as a result of its effect on the neuronal cells,
which will be described in detail later. It is a restricted
Chinese medical drug to be used, but not prohibited in
Hong Kong. erefore, it is important to investigate in-
depth the effect, toxicity, risk, and treatment related
Open Access
Chinese Medicine
*Correspondence: ckwang@hku.hk; yfeng@hku.hk
School of Chinese Medicine, The University of Hong Kong, Hong Kong,
China
Page 2 of 14
Chanetal. Chin Med (2021) 16:61
to the toxification of the Aconitums. In this review, we
retrieved literature from the PubMed database and sum-
marized the traditional use and the recent advances in
the investigation of toxicity, toxicology and processing
to detoxification of Aconitums. With a clinical-oriented
aspect, we also focus on the clinical symptoms and
management of Aconitums intoxication in humans. e
toxicokinetic information of Aconitum alkaloids is inves-
tigated by Yang etal. in the recent article [10], and that
would not be covered in this review.
Ethnophamracological relevance ofAcontitum
toxicity
The use ofAconitums intraditional medicine
China has a long history of using Aconitum as a herbal
drug. It was first recorded in Shennong’s Materia Med-
ica, the very first Chinese herbal medicinal classic dated
around two thousand years ago. More detailed infor-
mation, taxonomy, usage on the species Aconitum car-
michaeli Debx. derivatives Chuanwu (Radix Aconiti
praeparata) and Fuzi (Radix Aconiti lateralis praeparata)
were illustrated in another classic “Shanghan Lun” writ-
ten by the master Zhang Zhongjing in the Eastern Han
Dynasty [11]. It was classified as a “lower-class” drug,
and marked as “very poisonous” that must be used with
extreme care. e Aconitum species were categorized as
the “warm” drugs, that can power up and energize the
body, dispel moisture and humidity, as well as ease pain.
Fuzi was included in more than 20 herbal drug formulae
[12]. e amounts of Chuanwu and Fuzi that could be
prescribed to a patient were listed in the traditional mate-
ria medica. For Chuanwu, the amount should be 1.5 ~ 3g
(translated to Standard Unit) in formulation, while used
as a single drug should not be more than 2g. e amount
of Fuzi could be as high as 15g, as the toxicity of Fuzi
is less toxic, especially in the processed form. In recent
years, prescribing Fuzi becomes one of the most crucial
schools of thought in Chinese medicine.
Apart from the physicians from the past, Aconitum
herbs were also used locally as folk medicine or supple-
ment. People from the rural villages in the Qinling Range
of the Shaanxi Province in China used to cook and con-
sume A. carmichaeli before winter [13]. ey had a say-
ing that taking the herbs will give them warmth during
the winter, and also energy for everyday work. ey
would not cook the herb like other vegetables, but cut-
ting the root into slices, and boiling in a soup. e soup
was kept boiling to dry up and added water back several
times. e whole process should last for hours to several
days. ey claimed very few people felt unwell after con-
suming Aconitum in this way.
Other than the ancient Chinese, Indian also has a
long history in alternative medicine, or non-allopathic
medicine [14, 15]. ere were different systems of medic-
inal practice including Unani, Siddha, Ayurveda, etc., but
would not be discussed in detail here. ey have Aconi-
tum herbs introduced as drugs, and they also realized the
toxicity of aconitine (AC). Before the usage of the herb,
the Indian would boil the root of the plants with cow’s
urine for two days. It is then washed with water and
boiled again with milk for two more days. After that, the
residue will be cut and dried. ey preserved the prod-
uct in powdered form. e Indian used Aconitum herbs
to combat fever, inflammation, emesis and diarrhoea
[16]. However, toxic injured and fatal cases are reported.
It is observed that boiling for a prolonged time is a rural
method of processing the Aconitum herb to reduce
toxicity.
Traditional processing methods ofAconitum inTCM
Paozhi is the Chinese term for processing crude herbal
drugs using specific methods, that can reduce the toxicity
of the drug while maximizing its effectiveness. ere can
be more than one method to process the same herb, that
can bring about different pharmacological functions [17].
In this review, only the processing methods of Aconi-
tum carmichaeli Debx. herb would be reviewed (Fig.1).
e raw plant Aconitum carmichaeli are commonly cul-
tivated in the Sichuan Province, but also natively found
in Russia, Japan and other East Asia region [18]. It is a
perennial plant that has a purple in colour flower which
could be 60–150cm tall when mature completely. is
plant is usually grown on a grass slope, in between
bushes. e underground tuber root should be collected
in early summer, from June to August, just before the
flowering period. is plant could be derived into three
different types of herbal drugs, namely “Shengchuanwu”,
“Zhichuanwu” as well as “Fuzi” [19, 20], according to the
Pharmacopoeia of the People’s Republic of China, 2020.
“Shengchuanwu” is derived from the mother root of
the radix plant by drying, “Zhichuanwu” is the processed
form of “Shengchuanwu”, while “Fuzi” is processed from
the daughter root of the same plant. “Shengchuanwu” is
produced rather simple by drying under the sun after the
lateral roots, sand and soil are removed. When tasted on
the tongue, one should feel slight numbness. From the
raw “Shengchuanwu”, the large root part is soaked into
water, then boiled for 4–6h or steamed for 6–8h, and
then sliced and dried under the sun. is processed form
of Chuanwu is the “Zhichuanwu. On the other hand,
“Fuzi” and its derivatives are much more complicated.
“Fuzi” means attached offspring in Chinese, which is the
daughter root of the radix. Fuzi itself are poisonous as
well, therefore it must be processed before use. e crude
Fuzi, which is also called “Nifuzi” or “Zhifuzi”, is selected
lateral roots with soil and sands removed. It could be
Page 3 of 14
Chanetal. Chin Med (2021) 16:61
further processed into five different herbal drugs. “Yan-
fuzi” is made by soaking Nifuzi into saline with repeti-
tive drying until it is hardened and the surface is coated
with salt crystals. “Heishunpian” is another type of pro-
cessed Fuzi, which in addition to soaking in saline, it is
also boiled and stained to become dark, or black in col-
our. ey should be dried under the sun and will have
no numbness feels when tasted. e third one is “Baifu-
pia n ”, which are produced using the root with the bark
skin removed. ey are boiled in saline as well and dried
under the sun. To enhance its white colour, sometimes
the product will be steamed with sulphur. e fourth one
is “Danfupian”, which is made by washing the Yanfuzi in
water until the salt is complete removed, and boiled with
Licorice and black beans. e final one is “Paofupian”,
which is Fuzi processed by deep frying in hot sands until
plump and slightly coloured.
ere are some other Aconitum species also used
for herbal drug, including Aconitum kusnezoffii Radix
(Caowu), Aconitum kusnezoffii Radix cocta. (Zhicaowu),
Aconitum kusnezoffii Folium (Caowuye), Aconitum
coreanum Rapaics (Guanbaifu) and Aconitum pendulum
Busch (Xueshangyizhihao).
Medicinal eects ofAconitum species
In TCM practice, herbal drugs are given to patients in a
compound formulation, instead of a single drug or com-
pound. According to the TCM theory, most of diseases
are induced by an imbalance of the inner “yin-yang” in
the human body. Different diseases are the results of dis-
turbance of different organ system, and so prescriptions
are usually given in a formulation. e complex com-
pounds present in the formulation could help the body
regain its original optimal state.
Eects inthecardiac system
In the school of Chinese Medicine, “huoshen”, which pre-
fers to use Aconitum a lot in many decoctions, this herb is
important to enhance cardiopulmonary functions. Other
than the toxic effect mentioned previously, as a drug, the
Aconitum herbs also bring beneficial effects to the cardiac
system [21]. As recorded in the Chinese Classics, the Fuzi
Fig. 1 Graphical abstract of the Aconitum toxicology and detoxification
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Chanetal. Chin Med (2021) 16:61
has the effect of “warming up and energize” bodies. is
could be described in modern medicine using the cardi-
otonic actin [22]. e major energy source of the cardiac
muscle is adenosine triphosphate, which is produced
mainly from cellular respiration in the mitochondria,
and a minority of them from glycolysis [23]. Adenosine
monophosphate-activated protein kinase (AMPK) is an
enzyme that regulates cellular energy homeostasis by
activating glycolytic and fatty acid metabolism [24]. Deng
etal. showed that Benzoylaconine (BAC) could promote
mitochondria accumulation and ATP production in a
dose-dependent manner. BAC could activate oxidative
phosphorylation related protein expression in various
organs including the heart, and increase oxygen con-
sumption. Other compounds are also involved, including
napelline, lappaconitine (LA) and 6-benzoylheteratisine
[25]. LA, and its metabolite N-deacetyllappaconitine
(DLA), showed antiarrhythmic actions while having a
lower toxicity. Mice have 500 to 100 times higher toler-
ance in terms of causing arrhythmia when comparing LA
and DLA to AC [26].
Shenfu Tang, Shenfu San, or Shenfu Injection (SFI), are
a series of herbal drug formulas that involve the usage
of Fuzi, as well as Ginseng (Radix ginseng) [27]. Both
of these drugs have very effective power in energizing
severe patients and help recover from chronic illness.
An example was to be applied to the treatment of anae-
mia in patients with lung cancer. After 14days of intra-
venous injection of SFI, the performance status of the
patients was generally improved when compared with
the control group, measured using the Karnofsky score.
In the meantime, the anaemia situation and immune
level were also improved [28]. It was also reported that
SFI (~ 10mg/24h, i.v.) had positive effects in the recov-
ery of patients suffering from myocardial infarction [29].
Sixty myocardial infarction patients were given the car-
diogenic shock and treated with an intra-aortic balloon
pump, and then half of them were given SFI. e result
showed that SFI significantly shortens the recovery time
of the patients, by reducing the inflammation response.
Analgesic eects
In TCM, processed Aconitum or Fuzi are used as an
analgesic agent when treating diseases like rheumatoid
arthritis [30]. It is shown that the alkaloids, other than
the toxic ones, in the plant have a different extent of anal-
gesic activity [31–33]. Researches indicated that AC, as
well as 3-acetylaconitine and hypaconitine (HA), were
the highest affinity to the sodium channel. When AC
molecules bind to the sodium channel, at site II, the ionic
flow through the channel will decrease. In that case, the
sodium ion influx is affected, which changes the selectiv-
ity of the channel. e opening of the sodium channel is
prolonged, which results in an extension, or even per-
manent depolarization of neurons. is corresponds to
blocking of synapse signally passage, and thus account for
the antinociceptive and analgesic effect of AC [34]. is
was found in the hippocampus, where neuronal conduc-
tion was inhibited. Nevertheless, these three compounds
are also having high toxicity. e ratio of ED30 to analge-
sia is similar to the LD50, only from two (3-acetylaconi-
tine) to six (AC) times. erefore, they are not suitable to
be considered as druggable analgesics. us, lappaconi-
tine (LA) shines as a better candidate for analgesics, due
to its low toxicity [35, 36]. LA has more or less level of
analgesic activity, when comparing to morphine, in dif-
ferent tests on mice and rats [37, 38].
e anti-inflammation action also assists in the analge-
sic effect in the treatment of some diseases, for example,
Fuzi alkaloids can mitigate the symptoms of patients with
allergic rhinitis [39]. Sneezing, nasal secretions and nasal
scratching were alleviated in the study, where the inflam-
mation of nasal mucosal cells was improved through
the decrease of histamine content. e use of Fuzi was
proven to be safe also in clinical application.
Chuanwu also has analgesic and anti-inflammatory
effect in oedema. In a mice model of carrageenan-
induced paw oedema, water extract of Chuanwu at
60mg/kg showed efficient inhibition in oedema [40]. It
was believed that mesaconitine (MA), which presented
as the highest concentration alkaloids in the sample,
responsible for the antinociceptive and anti-inflamma-
tory effects.
Eects ongynaecological disorders
In TCM practice, Fuzi has been used for regulating or
balancing the patients’ endocrine system [9]. It could
help alleviate many gynaecological symptoms, including
abdominal cramps, painful menstruation, irregular men-
struation [41], and other gynaecological disorders like
climacteric disorder. However, physicians should avoid
administering Aconitum drugs to pregnant women, as
AC has high toxicity to embryo development [42].
Poisoned symptoms andtoxicology
Chemical aspects ofthetoxicology ofAconitum
e active compounds found in the Aconitum species
are mainly alkaloids, with three major groups namely
monoester diterpene alkaloids (MDAs), diester diterpene
alkaloids (DDAs) and lipoalkaloids. e most important
active constituents are C19-diterpenoid alkaloids and
C20-diterpenoid alkaloids. e compounds are served as
a double-edged sword because they are both toxic while
having medicinal beneficial effects.
e major toxic compounds are the DDAs includ-
ing AC, MA, and HA. DDAs are a type of diterpene
Page 5 of 14
Chanetal. Chin Med (2021) 16:61
alkaloids, which shares a C19 norditerpenoid skeleton [43,
44]. e skeleton chemical structure is shown in Fig.2a.
e aconites all having the same skeleton, but with dif-
ferent side chains as functional constituents substituted
at different sites. Wherever an acetyl group and a benzoyl
ester group are attached to C-8 (R6 in Fig.2a) and C-14
(R7), the alkaloids would be toxic. AC is a typical exam-
ple (Fig.2b). ey are the most toxic compounds among
all the alkaloids found from the herb. MDA, including
benzoylaconine (BAC), benzoylmesaconine (BMA) and
benzoylhypaconine (BHA), in comparison, has a lower
toxicity level and thus the medicinal value is higher.
ere is no acetyl substituent in the C-8 (R6) in MDAs,
which is usually replaced by a hydroxyl group (e.g. BAC,
BMA, BHA) [45, 46]. Alkaloids consist of different struc-
tures and functional groups will exhibit different activ-
ity in the body. From which, compounds with cardiac
activities are generalized by Jian etal. in 2012 [47]. For
C19-diterpenoid alkaloids without ester groups, an alpha-
hydroxyl group at C-15 (R9), a hydroxyl group at C-8 (R6),
an alpha-methoxyl or hydroxyl group at C-1 (R1) and an
amine or N-methyl group in ring A could bring possible
cardiac activities.
AC is extremely toxic to human, which will cause death
with just 2mg, while the toxic dose is only one-tenth of
that [48]. HA, however, is the most potent toxic com-
pound, which exists in a relatively lower proportion. e
diterpene alkaloids have either a hydroxyl, acetoxyl or
fatty acid acyl group as functional groups, while the effect
of many of the compounds is not yet been investigated
(Table1).
Clinical symptoms ofAconitum poisoning
Typical symptoms of patients poisoned by aconite deriva-
tives include nausea, vomiting, palpitation, arrhythmia
[49], muscle dysfunction, perioral paranesthesia, respira-
tory tract infection and pain, breathing difficulties, con-
vulsion, gastrointestinal upset [50, 51], and even shock
and coma [52, 53]. It is of course lethal in serious cases,
which are usually the result of ventricular arrhythmia.
ere is no direct antidote to aconitine poisoning, only
vital supportive measures could be provided to alleviate
the situation.
Toxicology ofAconitum
e toxic diester diterpene alkaloids (DDAs) found in
Aconitum are well known to affect mainly cardiac func-
tion as well as the central nervous system. e DDAs,
especially AC, inhibit the inactivation of the voltage-
dependent sodium channel by the substitution into a
binding site [44, 54]. e binding site is located on the
alpha-subunit of the sodium channel protein, which is
the specific neurotoxin binding site 2. e sodium chan-
nel is thus paralyzed, and the ionic difference, so as the
action potential cannot be built up. is leads to the dis-
ruption of neurotransmitter release, and thus the neural
signal transmitting pathway is disturbed [55]. e nerv-
ous system, as well as cardiac and muscular tissue, is
observed to be affected mostly and fatally. e toxicity
level of some of the compounds isolated from the herbs
is listed in Table2.
Interestingly, aconitine becomes a well-known activator
of the sodium channel, and is used to be an experimental
means to study the function of the sodium channel in the
past decades [56].
Toxicology inthecardiac system
Aconite poisoning could be fatal because it affects car-
diac function in the way of arrhythmia [57]. Observed
symptoms of cardiovascular toxicity include hypotension,
chest pain, arrhythmias, palpitation and sinus tachycar-
dia. Due to the effect of DDAs on the sodium channels,
their openings are prolonged or disrupted. e calcium
and sodium ion exchange through the membrane of the
myocardium makes the signalling depolarization and
repolarization delayed, which causes arrhythmia. e
Fig. 2 Toxic compounds in Aconitum. a General chemical skeleton of DDAs. b Chemical skeleton of Aconitine
Page 6 of 14
Chanetal. Chin Med (2021) 16:61
signals could not be transmitted through the vagus nerve
normally, as long as the acetylcholine level could not be
controlled at will [58]. e nerves in the cardiac system
are affected by prolonging excitation, and thus arrhyth-
mia occurs. Hypotension and bradycardia will occur as a
result [59, 60]. Furthermore, the ventromedial nucleus in
the hypothalamus could be activated by AC, which will
lead to hypotension and bradycardic action [61, 62]. It is
also responsible for the slowing down of the circulatory
system [63, 64].
AC is sometimes used as an induction agent to arrhyth-
mias in the study of the effect of antiarrhythmic drugs.
With different well-studied dosage, AC can create
ectopic, tachycardia, fibrillation, torsades de pointes, or
even death [65].
Noticeably, the above mentioned toxic effects are
majorly caused by AC, MA, and HA. Different alkaloids
found from the Aconitum have the opposite effect, which
shows low toxicity but a high medicinal value (will be dis-
cussed in the following session).
Toxicology intheneural system
e neural system is affected in a similar way as illus-
trated above [66, 67]. e neural transmitting pathway is
Table 1 Effective dosages of Aconitum herbal extract and compounds
Eect Herb/Compound Species Dose Ref
Cardiotonic Effect
Aconitine Mouse 5.69 ~ 8.49 ug/kg [119]
Hypaconitine Rat 250 ng/mL [120]
Higenamine Rat 5‑10 mg/kg [121]
Arrhythmic Effect
Aconitine Cat 20‑40ug/kg [58]
Aconitine Rat 1.46 mg/kg [122]
Anti-arrhythmic Effect
Hypaconitine Rat 0.5 mg/kg [123]
Lappaconitine Mouse 1.2–3.8 mg/kg [124]
Anti-inflammatory Effect
Aconitine Human ~ 10 mg/24 h, i.v [29]
Mesaconitine Mouse 0.2–0.5 mg/kg p.o [51]
3‑acetylaconitine Mouse 0.18–0.3 mg/kg [125]
Lappaconitine Mouse 6–8 mg/kg p.o [126]
Analgesic Effect
Aconitine Mouse 25 ug/kg [127]
Aconitine Mouse 60 ug/kg [128]
Mesaconitine Mouse 39 ug/kg [128]
Hypaconitine Mouse 10 ug/kg [128]
Pyrojesaconitine Mouse 78 ug/kg [128]
Antinociceptive Effect
Aconitine Mouse 0.028 mg/kg [34]
Mesaconitine Mouse 0.025 mg/kg [129]
3‑acetylaconitine Mouse 0.097 mg/kg [34]
Lappaconitine Mouse 2.7 mg/kg [34]
Hypoglycemic effect
Aconitan Mouse 100 mg/kg [127]
Anti-oedema Effect
A. Carmichaeli Mouse 60 mg/kg [40]
Anti-tumor Effect
Fuzi extract Mouse 360 mg/kg [130]
Aconitum‑derived alkaloids A172, A549, Hela
cell lines 1ug/mL [131]
Raji cell line 3ug/mL [131]
Page 7 of 14
Chanetal. Chin Med (2021) 16:61
disrupted by the AC poisoning, that the neuronal signal
cannot normally pass through the synapse. is brings
limbs abnormal controls or even paralysis. e DDAs will
also cause strong contractions which can result in diar-
rhoea and abdominal pain [68, 69]. e toxin could also
bring damage to the central nervous system, which could
lead to temporary or long-term disorder in the brain. In
serious case, this can bring shock and coma.
Clinical aspects ofthetoxicology ofAconitum
Aconite poisoning has been a problem in the past dec-
ades, especially from the ingestion of the Aconitum plant.
ere were more than 41 poisoned cases reported in
Hong Kong from 2012 to 2017, and at least 53 patients
died because of Aconite poisoning in China [10]. e
toxic level of the wild herb is much higher and fatal than
the processed herbal drug, therefore the cases in the
past were usually very serious, causing deaths [57, 70].
Patients admitted to the hospital suspected of being poi-
soned by Aconitum plants, would show those characteris-
tic symptoms mentioned previously, for example, nausea,
vomiting, numbness, hypotension, and extra-systoles or
arrhythmia [71, 72]. ey would have to be monitored
carefully in the intensive care unit with ECG 24-h. In
serious case, the patient could result in tetraplegia [73].
Most patients who died of aconite poisoning were due to
the collapsed cardiac function, in those cases, the heart
beating actions were disrupted irregularly or slowed
down [52, 74, 75]. However, with suitable, accurate and
on-time treatment, patients who suffered from aconite
poisoning could usually be rescued and survived, with or
without some consequences [76–78].
Detoxication ofAconitum intraditional
andmodern ways
Detoxication byherbal‑herbal combinations
Traditional Chinese medicine is particular about syn-
drome differentiation, and the prescriptions have nearly
always more than one drug. e multiple drugs can not
only alleviate different symptoms of the patients but also
help retaining balance back. Moreover, the drug–drug
interaction makes the whole formulation suitable for a
single patient personally. Some drugs may be too “hot”
to use on their own and should be balanced with some
Table 2 Toxic dose and LD50 of the herbs and compounds in Aconitums
Herb/Compound Species p.o s.c i.p i.v Ref
Raw Chuanwu Mouse 18,000 mg/kg [127]
Aconitine Mouse 1.8 mg/kg 0.24–0.31 mg/kg 0.28–0.34 mg/kg 0.12 mg/kg [69]
Mouse 0.55 mg/kg [128]
Rat 0.102 mg/kg [127]
Rat 0.112 mg/kg [103]
Cat 0.07–0.13 mg/kg
Dog 0.5 mg/kg
Human 2‑5 mg [127]
Mesaconitine Mouse 1.9 mg/kg 0.19–0.22 mg/kg 0.20–0.23 mg/kg 0.10 mg/kg [69]
Mouse 0.25 mg/kg [128]
Mouse 0.068 mg/kg [129]
Rat 0.158 mg/kg [103]
Hypaconitine Mouse 5.8 mg/kg 1.1–1.3 mg/kg 1.0–1.2 mg/kg 0.47 mg/kg [69]
Mouse 1.9 mg/kg [128]
Rat 0.291 mg/kg [103]
Benzoylaconitine Mouse 70 mg/kg 23 mg/kg [69]
Rat > 20.2 mg/kg [103]
Benzoylmesaconine Mouse 810 mg/kg 230 mg/kg 240 mg/kg 21 mg/kg [69]
Rat > 18.7 mg/kg [103]
Benzoylhypaconine Mouse 830 mg/kg 130 mg/kg 120 mg/kg 23 mg/kg [69]
Rat > 20.4 mg/kg [103]
Lappaconitine Mouse 5.9 ~ 11.5 mg/kg [124]
Jesaconitine Mouse 0.23 mg/kg [128]
Songorine Mouse 106 mg/kg [129]
Heteratisine Mouse 147 mg/kg [129]
Napelline Mouse > 147 mg/kg [129]
Page 8 of 14
Chanetal. Chin Med (2021) 16:61
“cool” adjuvants. Picking compatible drugs can not only
increase the drug efficacy but also reduce the side effects
or even toxicity of the formulation. Fuzi, for example, is
involved in some common prescription formula, includ-
ing Sini Tang (Gancao, ginger, Fuzi), as well as Zhenwu
Tang (Fuzi, ginger, Chinese peony (Paeonia lactiflora),
etc.).
Ginseng
Ginseng (Panax notoginseng) has the best combination
effect with Aconitum, in terms of detoxification and
enhancing drug action. In vitro experiment has shown
that Ginseng could reduce the metabolism of DDAs
through inhibition of CYP3A4 expression and activ-
ity [79]. In a rat model, Ginseng could slow down the
metabolisms of DDAs from Fuzi when given orally [80].
Ginseng combines with Fuzi could increase SOD activity
and reduce malondialdehyde (MDA), nitrogen oxide and
lactate dehydrogenase, which could enhance cardiac cell
viability [81]. rough modulating the action of CYP2J3,
CYP4A3, and CYP4F11, ginseng could reduce the toxicity
of Fuzi and AC to the heart and cardiac cells [82]. When
combines with Fuzi, Ginseng could reduce the LD50 more
than Licorice [83].
Gancao
Gancao (Radix glycyrrhiza sp.), also known as liquorice,
is another herb that has been used with the combina-
tion of Aconitum for hundreds of years. Liquorice extract
could induce the function of CYP3A4 and CYP2B6,
which can increase the efflux of AC out of the cells via
P-glycoprotein [84]. Glycyrrhizin and glycyrrhetinic acid,
compounds extracted from gancao, has a potent anti-
oxidant effect, which could reduce the cardiac-toxic lipid
peroxidation reaction by free radical scavenging [85].
Glycyrrhetinic acid could enhance the anti-apoptotic
protein Bcl-2 expression, and reduce pro-apoptotic and
pro-inflammatory cytokines such as Fas, Bax, TNF-α and
IL-1β, which results in cardiac protection [86]. e com-
bination of gancao with Fuzi reduce inflammation and
ventricular remodelling while enhancing survival in the
mice model via TLR4/NF-κB pathway [87].
Ganjiang (Dried ginger)
Ganjiang (Zingiberis rhizoma) combined with Fuzi pos-
sess a beneficial therapeutic effect against heart failure by
increasing mitochondrial biogenesis via Sirt1, PGC-1α
and NRF1 [88]. Ganjiang in combined with Fuzi, has
a better cardiac promotion effect than Fuzi alone, by
reducing H2O2 damage and MDA level, while increasing
intracellular SOD [89]. e therapeutic effect on heart
failure has risen, hemodynamics is enhanced, abnormal
activation of neuroendocrine is inhibited [90].
Dahuang
Dahuang (Rhei Radix et Rhizoma) significantly reduced
the DDA levels when combined with Fuzi and its deriva-
tives [91]. e side effects of arrhythmia by Fuzi such as
ventricular premature beats and ventricular tachycardia
were alleviated in a dose-dependent manner by Dahuang.
e effect is increased with the ratio of Dahuang to Fuzi
increases, and the level of toxic alkaloids is reduced [92].
Apart from the above four herbs, Fangfeng (Saposhnik-
oviae radix), Huangqi (Astragali radix), Yuanzhi (Polyg-
alae radix), Baishao (Paeoniae radix alba) also shown
increase the LD50 and TD50 to different extents, when
combined with Fuzi.
Herbs incompatible withAconitum
In addition to the enhancement of drug effect with
reduced toxicity, some herbs are incompatible with Aco-
nitum. In TCM, eighteen herbs that are incompatible
with each other were arranged in rhythm named “18
incompatible medicaments”. In which, Beimu (Fritil-
lariae cirrhosae bulbus), Gualou (Trichosanthis fructus),
Banxia (Pinelliae rhizome), Bailian (Ampelopsis radix),
Baiji (Bletillae rhizome) were regarded to be incompati-
ble with Aconitum. ese five herbal drugs were not toxic
by themselves. Analysis showed that the cardiotoxicity
of Heishunpian increases when combined with the five
drugs above [93].
Monitoring toxicity level andquality control
It is found that the herb–herb interaction of Aconitum
containing formulation could result in significantly dif-
ferent pharmacokinetic fate invivo [94]. is explained
why TCM prescriptions usually involve a combination of
different drugs and having specific predesigned combi-
nations of drugs that are listed. For example, the use of
Mahuang and Fuzi together could result in a lower alka-
loids plasma concentration, but not BAC which is the
active compound, when comparing to the use of either
one single drug extract [95]. erefore it is safer and
more efficient to use more than one drugs in a specific
combination. However, it is worth mentioning that the
elimination value and time increased as accumulation
may occur during continuous drug intake. It is essential
to monitor the patient’s situation before prescribing long
term usage of herbal medicine.
Research demonstrated the role of P-glycoprotein
(P-gp) which is encoded by the gene Mdr1 in the toxi-
cology of AC [96]. From the experiment, the group of
Mdr1a−/− mice showed higher analgesic and toxic effect
compared to the normal mice. e level of brain and
heart damage, measured by s100-B protein and creatine
kinase level, were significantly higher. e histopatho-
logical examination also agreed with the result, which the
Page 9 of 14
Chanetal. Chin Med (2021) 16:61
half-life of AC in the knock-down mice was dramatically
higher. It is believed that P-gp is involved and responsible
for the efflux of AC [97].
Due to the high toxicity level of the Aconitums, it is
very crucial to have a well-developed and monitored
method and system to check the quality of the herbal
drugs. e method should cover both qualitative and
quantitative aspects well, and help correctly processed
and detoxify the medicine [98]. Liquid chromatography
is one of the “golden” standards in TCM quality check,
and it is again useful in the management of Aconitum
derived drugs [99]. According to the Pharmacopoeia of
the People’s Republic of China, moisture content should
be less than 15%. By the means of HPLC using isopro-
panol-ethyl acetate as the solvent, the amount of DDAs
should be determined no more than 0.020% in the pro-
cessed Fuzi, and the amount of MDAs should be at least
0.010%. For processed Chuanwu, the amount of DDAs
should be no more than 0.040%, while MDAs at the range
of 0.070 ~ 0.15% [19].
Detoxication byprocessing
e toxicity of the drug is greatly reduced even after sim-
ple boiling. e amount of AC found in the herbs were
lowered after boiling from 10min to 2h, with an increas-
ing level of detoxification by the lengthen of time [30,
100, 101]. e process involves mainly the hydrolysis of
the DDAs into less toxic monoesters. After 2h of boil-
ing, the Baifupian showed no toxicity to the experimen-
tal mice at all, while in the 30 and 60min group there
were measured LD50 values. By using HPLC, no AC and
very few MA and HA were detected in the 2-h boiling
sample. e absence of change in total alkaloid amount
found in different boiling time suggested that the toxic
compounds were transformed into less toxic derivatives
through processing. e experiment also showed that
there is no significant difference in the treatment efficacy
in different boiling time, suggesting boiling can enhance
the safety of consuming the drug while keeping its effect.
Different methods are having different advantages
and disadvantages. Boiling is the easiest, but many use-
ful chemicals will be lost by dissolving in water [102].
Cooking or baking could preserve most of the active
ingredients, which at least affecting the pharmacologi-
cal functions. With the advancement of technology,
the methods of processing are being re-investigated.
Although having very low to undetectable level of DDAs
in the Paofuzhi samples prepared by method recorded in
the Pharmacopoeia 2015, the level of MDAs was found to
be lower than that of raw Fuzi [103, 104]. is is a sacri-
fice of the function by reducing the toxicity.
A study published recently analyzed the efficacy of
detoxication and enhancement of medical effects by
different processing methods, Shengfuzi, Paofuzi, and
four methods inspired by master Zhang Zhongjing,
including traditional dry-baked, modern baked, stir-
fried, and sand-burnt [104]. e four methods were pre-
pared from crude Fuzi (Shengfuzi), in order to imitate
the prescription ideas provided by Zhang. e results
showed that the “Zhifuzi” produced by the four novel
methods had a detectable low and safe amount of DDAs,
while dramatically higher amount (three to four times)
of MDAs were present. Another study in 2013 had simi-
lar results [103]. It suggested that the toxicity level of the
processed Fuzi have no differences in the steaming or
stir-fried herbs with or without saline. Using both meth-
ods, the DDAs amount could be greatly reduced by forty
to eighty times at the safety level. e difference comes
in the functional MDAs part, in which the amounts of
MDAs increase were as much as five times in the non-
saline-treated Fuzi, compared to the insignificant differ-
ence in the saline-treated Fuzi, as the traditional method.
MDAs have a much lower toxicity level, but similar level
of efficacy. It was also suggested in the article, that the
MDA/DDA ratio should be considered in the quality
control of processing Aconitums.
And finally, steaming, or autoclaving is the newest
technique to detoxify the Aconitum. e crude herbs are
steamed at 127 °C under 0.15 mPa high pressure. e
optimum steaming time should be 60 to 90min, where
toxicity and efficacy could remain balance [105]. ey
are capable to reduce most of the toxic compounds to
less toxic ones, which is the most effective way to make
the drug safe to use [106]. e total alkaloids amount and
thus the function of the herb do not reduce much. is
method is fast and clean, while easy to monitor the qual-
ity, as well as cost-effective. It is most commonly used to
prepare Chuanwu nowadays [107].
It is always crucial to know how a drug or compound
being digested and taken into action inside our body.
It is also important to keep track of the fate of the sub-
stances, pharmacokinetics is the study of this. As a toxic
herbal drug, we must learn how efficient our bodies
can eliminate the harmful compounds before the drug
can be safely used and prescribed. Using the method of
ultra-performance liquid chromatography-tandem mass
spectrometry (UPLC-MS/MS) [108, 109] or liquid chro-
matography-electrospray ionization-tandem mass spec-
trometry (LC–ESI–MS/MS), the alkaloids residue from
the drug in the blood serum could be detected and meas-
ured fast and accurately.
Clinical management ofAconitum‑poisoned cases
As mentioned previously, Aconitum poisoning is a seri-
ous issue. e consequences are huge for patients suf-
fering from poisons such as AC. is occurs usually by
Page 10 of 14
Chanetal. Chin Med (2021) 16:61
accidentally ingest the wild plant, or unprocessed Aco-
nitum, or wrong prescription given by physicians. Lives
are threatened because the DDAs are toxic to the heart,
neural and gastrointestinal system. When cardiovascular
function collapse, the patients are in danger [110].
When the patients suffer from tachyarrhythmia, they
would feel dizzy and palpitations occur. It could result
in cardiac arrest or myocardial infarction. A 61-year-old
man was observed with the above symptoms [111]. e
patient was having back pain in the previous 3months
and got prescribed Chinese herbal medicine as analge-
sics. After consuming a portion of the drug for 1 h, he
suffered a lot and admitted to the hospital. He had hypo-
tension, with tachycardia. Lidocaine 100 mg was given
immediately, and then with continuous infusion. How-
ever, the situation did not improve, and further amiodar-
one was infused additionally for 36 h. e arrhythmia
problem was alleviated and later recovered without other
consequences. is was an essential case to prove the
usefulness of amiodarone in treating aconitine poison-
ing induced ventricular tachyarrhythmia. As there is no
direct antidote to aconitine poisoning, essential vital sup-
port and treatment must be given accurately and effec-
tively. Some other clinical evidence also proved the effect
of Flecainide, another antiarrhythmic agent, on treating
aconitine poisoning induced ventricular tachyarrhythmia
[111].
Another worth mentioning case study was a Caowu
poisoning that happened on a 48-year-old Chinese man
[112]. He consumed some herbal medicinal wine before
admitting to the hospital accident and emergency depart-
ment. He felt chest pain, numbness all over the body, and
then dyspnea. Apart from the typical cardiac toxicity,
the patient suffered from polycystic renal haemorrhag-
ing as well, due to a family history of kidney disease. e
patient was given acticarbon, atropine and intravenous
injected lidocaine. e injection lasted for almost 5h but
the prognosis was still poor. Hemoperfusion was car-
ried out instead. e heparin level was lowered to none
and half in the two perfusion device respectively. Meth-
ylepinephrine was given to maintain blood pressure.
e arrhythmia improved around 2h later, but ventric-
ular bigeminy remained. On the third day after admis-
sion to the hospital, the kidney haemorrhage was finally
under control. He left the hospital 1week later. is case
emphasizes how important supportive therapy is when
dealing with poisoning cases. Blood purification removes
the aconitine from the body, and help retaining normal
cardiac function. It can also sensitize the heart to antiar-
rhythmic drugs [77].
A 92-year-old woman took a herbal decoction con-
taining Fuzi to treat her mood swings and maintain
health, and was soon appeared to be life-threatening
with bradycardia and hypotension after 1h [113]. ECG
showed ventricular abnormalities, including sinus brad-
ycardia and low-P wave. e patient was treated with
an infusion of saline and inotropic agents for one day,
and those symptoms were alleviated and the condition
backed to normal. e key to saving patients from aco-
nite poisoning is to find out the poisoned substance as
soon as possible, and prescribe with appropriate alleviat-
ing agents.
Discussion
In the past, the ancient Chinese wrote the materia med-
ica by trial-and-error. ey recorded the usage and phar-
macological safe amount and level by experience and
tested for the herb-herb combinations one by one until
a typical formulation could be concluded. ey passed
down the methods of processing through generations
and improved by years. Case of Aconitum poisoning was
reported in the modern era as early as 1867 and onwards
the toxicity of Aconitum has caught more and more atten-
tion besides its documented therapeutic effects. A recent
study that reviewed 40 cases reporting Aconitum poison-
ing in mainland China from 2004 to 2015 suggested that
a majority of the cases appears in persons who believed
the medicinally beneficial effect of Aconitum in its toxic
form [50]. e dosing issue that brings attention to the
therapeutic index of Aconitum between its pharmacolog-
ical and toxic limits is therefore critical to the safe use of
the herb in clinical practice. A local review from the Hos-
pital Authority of Hong Kong on 52 cases of Aconitum
poisoning from 2004 to 2009 suggested that overdosing
is the major underlying cause of poisoning [114]. ere
were five recent cases of aconite poisoning from 2016
to 2017, that the patients received medication from the
Chinese Medicine Centre of Hospital Authority [115].
ey were dispensed with normal doses of processed
Fuzi but appeared to have symptoms from mild numb-
ness to hypotension. Two of them exhibited bradycardia
and were attended in the intensive care unit. ey recov-
ered fully after treatment. A report in 2006 recorded the
situation that there were 10 cases of aconite poisoning
from 2004 to 2006, however, four of them were not pre-
scribed Aconitum herbs in the formulation [116]. is is
a problem that we must face if there was contamination
happened in the herbal medicine, or the quality control
failure. In the view of safety control, developing a strict
quality control with an indicated range of certain sub-
stance in Aconitum may be optimal, however, due to the
inconsistency of chemical composition between batches
and the narrow therapeutic index, the optimal safe range
of Aconitum substances may be too narrow to be prac-
tical. On the contrary, with the aid of modern science,
the functions and properties of an herbal drug could be
Page 11 of 14
Chanetal. Chin Med (2021) 16:61
explained and proved by extracts or isolating single com-
pounds. Developing safer methods to detoxify the herbal
drugs and enhance drug efficacy in the meantime are
beneficial to the society.
Technological advancement has different views on
processing methods. e recent studies showed that
Fuzi processed without soaking in saline have better
medicinal effects while keeping the safety level [103, 104].
is is inconsistent with ancient wisdom but could be
explained by a few reasons. e safety could not be eas-
ily monitored by simple baking of crude herb, as the tem-
perature and condition may not be maintained well in the
past. Also, the high salt content in herbal medicine helps
increase the storage time of the drug. Finally, the quality
check of the drug may be easier, as the appearance of the
processed drug would be completely different. e Phar-
macopoeia should consider introducing or replacing the
current method of Fuzi processing since the technology
level of the pharmaceutical industries has improved a lot.
A single herb could be either an advantageous drug,
or a lethal poison at different doses and forms, so it is
essential to determine the optimum dosage for a spe-
cific disease or case. Traditional Chinese Medicine is
inherited for thousands of years, and modern sciences
minimize the risk when using herbal medicine. Both are
indispensable in the development of pharmacy; the tra-
ditional wisdom provides hints and directions to drug
development, while modern medicine brings the knowl-
edge to the next level. Herbal-herbal combination to
reduce toxicity could be a good point to research deeper
into because it requires no additional treatment on a sin-
gle drug. For example, the alkaloid in Fangji (Stephania
tetrandra) could inhibit the movement of calcium ions
crossing the L-type calcium channel, which in turn lower
the toxic effect causing arrhythmic of aconite alkaloids
[117]. e addition of the combination is an alternative
way to detoxify and increase the safety of toxic herbal
drugs, and this is valuable in pharmacological develop-
ment. On the other hand, different ratios of combina-
tion with other drugs could result in different toxicity on
Aconitum herbs. e five herbs in the “18 incompatible
medicaments” were claimed not to be used together with
Aconitum. However, recent studies reviewed that when
combining with different ratios, the toxicity of the combi-
nation may not increase [118]. More scientific researches
on the topic are needed to illustrate the mechanism of
herb-herb combination effects on toxic drugs, not only
for Aconitum.
Conclusion
In this review, we update the knowledge advancement
about the toxicity and toxicology of Aconitum drugs. e
drug has been widely used in ethnomedicine especially in
China despite its toxicity. It has anti-inflammation, anti-
arrhythmic, analgesic and some other effects as a medi-
cine. Increasing evidence has shown the benefits of using
Aconitum herbs in treatment. However, the risk of car-
diotoxicity causing arrhythmic, gastrointestinal upset, or
even tetraplegia and death is a serious concern. e poi-
soned cases were usually caused by inappropriate usage,
overdose, long term consumption, or herbal drug of poor
quality. Cases are studied and the prescription of west-
ern antiarrhythmic drugs such as amiodarone or atropine
is an immediate response to save lives. Furthermore, the
current methods of Aconitum processing are discussed
and reviewed. It is concluded that the standard process-
ing method written in the China Pharmacopoeia may
not be the best one in terms of enhancing the medicinal
effect of the drug, and more researches should be done
on reflecting the effectiveness. With the correct ratio to
combine Aconitum with other herbal drugs, such as Gin-
seng, Gancao, Ganjiang and Dahuang, toxicity could be
reduced and therapeutic effects could be enhanced.
Acknowledgements
Not applicable
Authors’ contributions
YTC and NW wrote the manuscript; YF designed, revised and finalized the
manuscript. All authors commented on the manuscript during the writing
process. All authors read and approved the final manuscript.
Funding
This research was funded by the Research Council of the University of Hong
Kong (project codes: 104003422, 104004092 and 104004460), Wong’s dona‑
tion (project code: 200006276), a donation from the Gaia Family Trust of New
Zealand (project code: 200007008), a contract research project (project code:
260007482), and the Research Grants Committee (RGC) of Hong Kong, HKSAR
(Project Codes: 740608, 766211 and 17152116).
Availability of data and materials
Not applicable.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Received: 23 April 2021 Accepted: 16 July 2021
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