Volume 13, Number 4 | Winter 2018

Research Review
Adverse Effects of Kampo Medicine

considerable side effects [1] 。 In the past, whenunexpected incidents occurred by the administration

Toshiaki Makino1) and Hiromichi Yasui2)of Kampo medicine, those are not recognized as1) Department of Pharmacognosy, Graduate School of
Pharmaceutical Sciences, Nagoya City University,
Nagoya, Japan
2) Japan Institute of TCM Researchadverse effects but the drugs used are prescribedunder incorrect diagnosis in the patient's symptomor the essential worse reaction to make a fullrecovery. However, now the adverse effect of Kampo

In the past in Japan, when unexpected incidents
occurredbytheadministration

of

Kampo

prescriptions, those are not recognized as adverse
effects but the drugs used are prescribed underincorrect diagnosis in the patient's symptom or the
essential worse reaction to make a full recovery.
However,now

theadverseeffectofKampo

prescriptions are well recognized, and when it
happens, the medication should be stopped andsuitable treatment is needed. The most frequent
adverse effect occurred by Kampo prescriptions isgastrointestinal disorders, and rehmanniae radix,
gypsum, ephedrae herba, and angelicae radix
sometime cause. In addition, drug eruption andcystitis due to allergy sinetunes occur with several
kinds

of

crude

drugs.

Furthermore,varioussymptoms caused by the sympathetic stimulation ofephedrine

contained

inephedraeherba,

pseudoaldosteronism caused by glycyrrhizae radix,
aconitine poisoning caused by aconiti radix processa,
interstitial pneumonia and drug-induced liver injury
causedbyscutellariae

radix,

mesentericphlebosclerosis caused by gardeniae fructus has
been reported.

allergy,

pseudoaldosteronism,

interstitial

pneumonia, drug-induced liver injury, mesentericphlebosclerosis

treatment is needed.
Kampo formula is a mixture of several crude
drugs, and their adverse effects can be explained by
the crude drugs contained therein. The side effects
that can be caused by each crude drug are described
below.
1. Gastrointestinal disorders
The most frequent side effects of Kampo
medicines are gastrointestinal disorders. Typicalcrude drugs that induce gastrointestinal disorders
includegroundrehmanniae

radix,

gypsum,ephedrae herba, angelicae radix, cnidii rhizoma, andzizyphi spinosi semen. Among them, rehmanniae
radix often causes anorexia, epigastric discomfort,
epigastric pain, diarrhea, etc. Ephedrae Herba also
causes anorexia and epigastric pain.
Most of these symptoms usually relieve if the
drugs

are

basically

stopped.

Kampo

administeredprescriptions

beforemeals,

arebutadministration after meals may avoid to cause such

2. Drug allergy
It is known that some crude drugs easily cause
allergic reactions to the living body. The mostcommon symptom is on the skin (drug eruption).

Japan has a centralized medical system centeredon Western medicine, and Japanese traditional
Kampo medicine is also used in this system. In
recent years, with the spread of Kampo medicines, it
has been found that Kampo prescriptions also have12

the medication should be stopped and suitable

symptoms.

Keywords: Kampo prescriptions, adverse effects,
drug

medicines are well recognized, and when it happens,

Rash or pruritus is sometimes caused by cinnamomi
cortex, ginseng radix, astragali radix, rehmanniae
radix, tritici fructus, oryzae fructus, dioscoreae
rhizoma, and perillae herba [2; 3]. In addition tothese crude drugs, there are reports on crude drugs

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

Volume 13, Number 4 | Winter 2018

and prescriptions that caused a rash upon taking

3. Licorice-induced pseudoaldosteronism

drugs. Drug allergies occur not only in crude drugs

Glycyrrhizae radix is the dried root and stolon,

but also in Western drugs at a certain rate, so it iswith (unpeeled) or without (peeled) the periderm, ofnecessary to pay close attention to the patient's

Glycyrrhiza uralensis Fischer or Glycyrrhiza glabra

medical history in order to prevent the occurrence.

Linné (Leguminosae), and it is commonly called as
licorice root. This causes pseudoaldosteronism with

<Case report>

some frequency. Therefore, it is necessary to pay

The patient is a 56-year-old man. A few years ago,

attention to physical findings (edema, increased

renal function was pointed out, but a doctor at a

blood pressure) during the administration and tovisiting hospital told him that his serum creatinine

measure potassium in the blood regularly. In Europe,level was so high that hemodialysis would be needed

where licorice is used as a food additive sweetener,

soon. Then, he visited my clinic on May 6, 20XX. The

this side effect has long been reported [5-8]. In Japan,

serum creatinine level was 5.78 mg/dl. I prescribed

the incidence of pseudoaldosteronism due to Kampo

him for yojinkodakuto. Astragali radix was 20 g.

prescriptions was said to be higher rate among

Creatinine continued to fall as expected, reachingelderly women. However, this is not true, and2.16 mg/dl on July 31. However, at this point, aalthough there are large individual differences in thestrong pruritic rash appeared on his entire body, andonset, it occurs in all generations regardless of

I was forced to discontinue the prescription. His

genderserum creatinine level began to rise gradually,

pseudoaldosteronism depends to some extent on thereaching 3.85 mg/dl on November 28, but when I

amount of licorice intake, and when using Kampo

administered the same prescription instead ofprescriptions containing 2.5 g or more of licorice per

astragali radix, the rash appeared two weeks later,day, be sure to pay attention to the onset of this side

serum creatinine dropped to 3.21 mg/dl.

effect. In addition, licorice is the most commonlyatprescribed
In addition, drug-induced cystitis has beenreportedforsaireito,

shosaikoto,

a

fixed

crude

rate

drug

[9].

in

The

Japanese

onset

of

Kampo

prescriptions. There is a possibility that thesaibokuto,

combination of Kampo prescriptions may not besaikokeishito, seijobofuto, and unseiin. It has been

noticed, or exceed amount when combined with thereported that the administration of these Kampo

use of licorice as a food additive.

prescriptions caused cystitis-like symptoms, such as
dysuria,dysuria,

pollakiuria,

pusuria,

Symptomsofpseudoaldosteronism

includeandhypokalemia, increased blood pressure, sodium/bodyhematuria [2; 3]. The pathological condition is drug-

fluid retention, edema, and weight gain. In severe

induced cystitis, i.e., eosinophilic cystitis withcases, it causes myopathy and rhabdomyolysis.

eosinophil infiltration. Some allergic mechanism has

Therefore, attention should also be paid to weakness,been speculated. As of 2011, 90 cases of cystitis weremuscle pain, limb spasms and paralysis, CK (CPK),

reported due to Kampo prescriptions in Japan, andetc. When licorice is used, serum potassium levels

among these prescriptions, 80 cases are using

should be measured sufficiently. If abnormalities areprescriptions including scutellariae radix [4]. Theseobserved, the administration should be discontinued,

are rare side effects, and withdrawal of the drug

andoften improves the symptoms promptly, but careadministration of potassium agents should be taken

must be taken.

as necessary. It also improves when used inappropriate

treatments

such

as

the

combination with aldosterone antagonists such as
eplerenone [10].

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

13

Volume 13, Number 4 | Winter 2018

The component that causes pseudoaldosteronism

patient said that after taking this prescription, urine

caused by licorice is glycyrrhetinic acid (GA), a

was flowing only once. I thought this was a adverse

metabolite of glycyrrhizin contained in licorice byeffect of ephedrae herba and stopped it immediately,

11β-

and i changed my prescription to ryutanshakoto. The

hydroxysteroid dehydrogenase (11β-HSD) 2 present

dysuria disappeared, and the pain of the first toe ofinthe left foot gradually resolved.

intestinalrenalbacteria.
tubularGA

inhibits

epithelial

cells,

type
and

the

accumulated cortisol activates mineralocorticoid
receptors, thereby excreting potassium to promoteWhenadministering

Kampo

reabsorption of sodium and sodium, resulting incontaining

ephedraetohypokalemia [7; 8]. However, since GA appears as a

circulatory disorders such as angina pectoris andmetabolite in the blood of all patients who takemyocardial infarction, with severe hypertension,licorice, it cannot explain the individual differences

renal

in the occurrence of pseudoaldosteronism, so a

hypertrophy, prone to insomnia, careful observation

search for a true causative substance instead of GA

and discretion should be taken not to exacerbate

was conducted, At present, glycyrrhetinic acid-3-O-

these diseases and conditions. The incidence of thissulfate, another metabolite of glycyrrhizin, isside effect has individual differences and dose-

estimated to be the causative substance [11], anddependency to some extent.

disorder,herba

prescriptions
patients

hyperthyroidism,

withprostatic

hypoalbuminemia is considered as one of the risk
factor to cause pseudoaldsteronism [12].

5. Aconite poisoning
Aconiti radix processa is the dried tuberous root

4. Palpitations, tachycardia caused by Ephedraeof Aconitum carmichaeli Debeaux or AconitumHerbajaponicum Thunberg (Ranunculaceae) prepared byEphedrae herba is the dried terrestrial stem of

the following processes. 1: Autoclaving. 2: Heating orEphedra sinica Stapf. This crude drug contains

autoclaving after rinsing in salt or rock salt solution.

ephedrine that is a similar chemical structure to

3: Treating with calcium hydroxide after rinsing inadrenaline and has a mixed sympathetic nervous

salt solution. Before processing, contains aconitine,system effect. The bronchodilating activity resulting

mesaconitine, etc., has strong analgesic activity, buttherefrom can be said to be a scientific basis for thealso has strong toxicity [13; 14]. By heat-processing,

medicinal effects of ephedrae herba, but adverse

aconitine and mesaconitine were hydrolyzed toeffects sometimes occur including hypertension,

become benzoylaconine and benzoylmesaconine,tachycardia, palpitations, insomnia, and urinary

respectively, and their toxicity were reduced about

retention.

1,000-fold

[14].

The

Japanese

Pharmacopoeia

describes the upper limits on the contents ofaconitine and mesaconitine in aconiti radix processa,<Case report>
68-year-old man. Two days ago, he arrived mythat makes it relatively safe to use, but may still

clinic due to severe pain accompanied by swelling at

cause poisoning in sensitive patients. The initial

the first toe of his right foot. Until now, it was

symptoms of sticking poisoning are numbness andpointed out that the uric acid level was high, but hepalpitations, and the patients with those symptoms

said that he had left it alone. I diagnosed a goutneed to stop using or reduce the dosage. Among theattack, and prescribed eppikajutsuto extract. The

preparations of aconiti radix processa marketed inpatient came to my clinic the next day, and although

Japan, some manufacturers produce the contents ofthe pain in the left first toe was alleviated, theaconitine and mesaconitine near the upper limit to14

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

Volume 13, Number 4 | Winter 2018

have high analgesic effect, but these products may

preparations is currently contraindicated. In aeasily cause side effects. On the other hand, thesurvey of Tsumura ethical shosaikoto extract

active ingredient of aconiti radix processa for

preparations from October 1995 to March 1997, 69

neuropathic pain is not the highly toxic alkaloid, butcases (2.8%) out of 2,495 patients were reported toneoline, an alkaloid that does not hydrolyze. [15].

have adverse effects including abnormal laboratory

Therefore, even if the heat treatment is performed

test.

well to completely decompose highly toxic alkaloids,<Case report>[18]it is also useful for neuropathic pain.

A 71-year-old woman was hospitalized with adiagnosis of pneumonia. She had fever, cough,<Case report>[16]The patient is a 78-year-old woman. Since X–31

dyspnea, and diffuse granular reticular shadows inyear ago, she has suffered from rheumatoid arthritis.

both lung fields on chest X-ray. I suspected summer-

She visited my clinic in the year X. Administration

type hypersensitivity pneumonitis, but I chose noofof

medication since the condition is not but. However,

unprocessed aconiti radix markedly improved her

her condition had been further exacerbated, I

joint pain and laboratory findings. However, thesuspected

joint pain was exacerbated on October 7th, X+2 year.

medications were discontinued and prednisolone

Then, the drug was changed to uzuto decoction

was administered. Chest X-rays improved markedly.

containing 4.5 g of unprocessed aconiti radix. On

Transbronchial lung biopsy showed interstitial

October 11th, one hour after the oral administration,

pneumonia, and lymphocyte stimulation test showedshepharyngeal

positive for shosaikoto. The challenge test revealed

strangulation, and vomited three times. Since thefever, hypoxemia, and the appearance of interstitialheart rate dropped to 60/min and the blood pressure

pneumonia on chest X-ray. This case report appears

dropped to 90 mmHg, blood vessels were secured andto be the first of drug-induced pneumonia caused by

the electrocardiogram was monitored. Although heshosaikoto.

daibofuto

decoction

developed

blurredcontaining

eyes

and

4.5

g

drug-induced

pneumonia,

and

all

did not receive any special treatment, it improved as
Following this report, the similar adverse effects

it was.

were seen in more than 15 Kampo extract
6. Interstitial pneumonia and drug-induced liver

formulations including scutellariae radix that is theinjury

dried

root

of

Scutellaria

baicalensis

Georgi

These side effects of Kampo medicines have been

(Labiatae), from which the periderm has beenreported since 1989. Prior to that, it may have been,

removed. Then, it was speculated that this adverse

but never mentioned. Of particular note was theeffect was probably due to scutellariae radix. It isreport that 88 patients who took Shosaikoto

predicted baicalin, which is contained in scutellariae

developed interstitial pneumonia in the three years

radix in relatively large amounts binds to albumin tosince 1994, of which 10 died. However, its frequency

become hapten, and that the sensitization isis extremely low, and according to Homma's research,

established. However, this is only a prediction andthe frequency of occurrence is almost 100,000 per 4

future research is required.

people / year [17]. Among them, most of the patients

Scutellariae radix has also been suspected to

had chronic hepatitis B and C, and interferon wascause drug-induced liver injury. Some patients have

used

the

increased ALT/AST in a short time after taking

concomitant use of shosaikoto and interferon

scutellariae radix [19]. Although the frequency isinalmostallpatients.

Therefore,

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

15

Volume 13, Number 4 | Winter 2018

extremely low, it is often asymptomatic. Therefore, it

Althoughinterstitial

pneumonia

and

drug-

is desirable to conduct a liver function test within a

induced liver injury caused by Kampo prescriptions

few weeks after administration of the preparation.

are not so frequent, these adverse effects should be

In addition, the cases of fever have been reported.

noted. When fever, cough, dyspnea, or abnormal lung

Fever is also a subjective symptom, and is relatively

sounds (fine crackles) appears, the administration ofeasy to find. It is reported by Terashi et al. [20].

Kampo prescriptions should be discontinued, chest

At present, about 40 kinds of Kampo formulas

X-rays should be immediately examined, and thethat caused liver disorders, and about 30 kinds ofappropriate treatment such as the administration of

Kampo formulas that caused lung disorders havecorticosteroids should be performed. It is also

been reported. It is said that these cases arenecessary to conduct liver function tests regularly torelatively common in the elderly, but this is notprevent drug-induced liver injury.

always the case, and the cause is thought to be due
to a specific constitution such as allergy. Therefore,

7. Mesenteric phlebosclerosis caused by gardeniae

the only way to prevent these adverse effects is tofructuscarefully detect and respond to the history of drug orItfood allergies at the time of drug administration.

has

been

reportedthat

mesentericphlebosclerosis caused by Kampo prescriptions. In

interstitial

2013, the Research group funded from Ministry ofpneumonia: Shosaikoto, daisaikoto, saikokeishito,

Health, Labor and Welfare conducted national

saibokuto,

Formulasreported

to

cause

saireito,

saikokeishikankyoto,

survey, and reported that over 80% of mesentericsaikokaryukotsuboreito,

hangeshashinshinto,

phlebosclerosis patients took Kampo prescriptions

hochuchuekkito,

containing gardeniae fructus. More than 90% of thegoshajimkigan, seihaito, shin’iseihaito, junnchoto,patients had taken the drugs more than 5 years [21].

seishinreshiin, boiogito, bofutsushosan, otsujito,

Gardeniae fructus is the dried fruit of Gardenia

shoseiryuto,

bakumondoto,

keigairengyoto,jasminoides Ellis (Rubiaceae). There are manysanoshashinto,

Kampo formulas containing gardeniae fructus, but

shakuyakukanzoto, daikenchuto, ryuchoshakoto.

the special attention is needed for eight formulas

Formulas reported to cause drug-induced

such as kamishoyosan and orengedokuto. If theliver injury and jaundice: Otsujito, daisaikoto,patients who have been taking these prescriptions

shosaikoto, shosaikotokakikyosekko, saikokeishito,

for 5 years or more have repeated abdominal pain,

saikokaryukotsuboreitoto,

diarrhea,

orengedokuto,
nijutsuto,

yokukansan,

unseii,gorinsan,saikokeishikenkyoto,

constipation,

abdominal

bloating,saibokuto, saireito, orengedokuto, sanmotsuogonto,

nausea/vomiting, or have positive fecal occult blood

shakuyakukanzoto,(asymptomatic),

hangeshashinto,

unseiin,itisnecessarytoconduct

shoseiryuto, maobushisaishinto, kakkonto, seihaito,

colonoscope and CT inspection. If there are

seijobofuto,

shin’iseihaito,

bakumondoto,

characteristic symptoms such as dark purple ornyoshinsan,

keishibukuryogan,kamishoyosan,bronze color on the mucous membrane at the rightrikkunshito, hochuekkito, ninjinyoeito, daikenchuto,colon, linear or dotted calcification along the colon

nijutsuto, juzentaihoto, boiogito, bofutsushosan,

wall or mesenteric vein on CT, the calcification ofjunchoto,

goshajinkigan,

venous wall and the increased collagen fibers in the

keigairengyoto, seishinrenshiin, yokukansan,

histopathology, the drugs should immediately beryutanshakanto,

discontinued. The prognosis is generally good by thegoreisan.

inchinkoto,sanoshashinto,

goshuyuto,

withdrawal of Kampo prescription, but it takes along time to improve fibrosis and calcification. In the

16

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

Volume 13, Number 4 | Winter 2018

case

of

long-term

administration

of

Kampo

and children is clinically experienced, it is better toprescription containing gardeniae fructus, it isuse

lactose-freedesirable to conduct a fecal occult blood test, regularsymptoms

colonoscopy once every 1 to 2 years, simple

gastroenteritis.

of

Kampo

preparations

prolongedfordiarrhea

the
after

abdominal CT test, etc. [22].
9. Aristolochic acid-induced kidney injury and cancer
It was reported in Belgium that people who took

<Case report>[22]The patient is a 65-year-old woman. In July in X

weight-loss herbal preparations developed kidney

year, she visited my hospital to take Kampo

injury that required dialysis and transplantation

medication for hepatitis C. Initially, hochuekkito had

between 1990 and 1992 [25]. In this preparation,

been

Aristolochia fangchi (Aristolochiaceae) that contains

administered,saikokeishikankyoto,

and

then

changedkeishibukuryogan,

to
etc.

aristolochic

acid,

which

are

nephrotoxic

andThereafter, the dosage of gardeniae fructus was

carcinogenic, was found. In Japan, there have been

temporarily reduced to 5 g/day, but had been soon

some case reports of kidney injury caused byreturned to 15 g/day and continued. At X+13 year,

Tokishigyakukagosyuyushokyoto preparation using

her cumulative intake of gardeniae fructu was 5,379

the stem of Aristolochia manshuriensis as ang for 9.4 years. There were no findings such as

ingredient instead of akebiae caulis, the dried stem

abdominal pain, abdominal distension, abdominalof Akebia quinata Decaisne or Akebia trifoliata

tenderness, etc., but under the patient's consent,

Koidzumi (Lardizabalaceae), and herbal dietarycolonoscopy was performed in May in X+17 year.

supplements containing aristolochic acid [26; 27].

Blue pigmentation and mild edema were observed on

At present, the distribution of crude drugs

the mucosa of the cecum, ascending colon, andcontaining aristolochic acid is banned not only intransverse colon. Histopathological test also showed

Japan but also in other countries. Therefore, it isincreased submucosal collagen fibers in the cecum,

thought that the toxicity of aristolochic acid will not

ascending, and transverse colon. This confirms theoccur with regular drugs. However, the possibility todiagnosis of mesenteric venous sclerosis

use the products distributed in unregulated internet
market or the old herbal product before ban is

8. Lactose allergy and intolerance

undeniable, care must be taken account.

Drug adjuvants such as excipients are containedin Kampo extract prescriptions. Commonly used

Conclusion

excipients are lactose, starch, cellulose and so on.

As descried above, Kampo medicines also haveAmong these, lactose contained only a small amountmany adverse effects. Diarrhea caused by rhei

of milk-derived protein as an impurity, which could

rhizoma, the dried rhizome of Rheum palmatum

be a problem for milk allergy patients. However,Linné (Legminozae), etc. or sal mirabilis, a mineraleven patients with relatively severe milk allergy

substance, mainly composed of sodium sulfate

have no abnormalities in the results of oral lactose

hydrate (Na2SO4•10H2O) is not adverse effect but

tolerance test [23]. Lactose intolerance has been

the excessive mistaken dosage. However, in clinicalreported to be less than 1% in ethical Kampo

practice, a wide variety of adverse effects from very

prescriptions using lactose as an excipient [24].

slight allergies to severe liver damage has been

Therefore, it is considered to be of little concern

experienced. These can be can be led quickly in aclinically.

lactoseshort period without any serious situation if theintolerance such as after gastroenteritis in infants

physician and pharmacist find it and perform

However,sincesecondary

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

17

Volume 13, Number 4 | Winter 2018

appropriate

treatment

immediately.

Careful9.

Yoshino, T, Yanagawa, T, Watanabe, K (2014)

observation is the best way to deal with adverse

Incident of pseudoaldosteronism. The generaleffects.

meeting of Medical and Pharmaceutical Society
for Wakan-yaku Abstracts. 8: 60.
10. The Japanese Society of Hypertension, 2009.

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