TraditionalOrientalHerbalMedicineforChildrenand ...2.3. Criteria for Considering Studies for This Review 2.3.1. Type of Studies. Randomized clinical trials of TOHM. The eﬃcacy of

Hindawi Publishing CorporationEvidence-Based Complementary and Alternative MedicineVolume 2012, Article ID 520198, 15 pagesdoi:10.1155/2012/520198

Review Article

Traditional Oriental Herbal Medicine for Children andAdolescents with ADHD: A Systematic Review

Yuk Wo Wong, Deog-gon Kim, and Jin-yong Lee

Department of Pediatrics, College of Korean Medicine, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu,Seoul 130-702, Republic of Korea

Correspondence should be addressed to Yuk Wo Wong, [email protected]

Received 23 July 2012; Revised 27 September 2012; Accepted 14 October 2012

Academic Editor: Jörg Melzer

Copyright © 2012 Yuk Wo Wong et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Objective. To evaluate the efficacy of traditional Oriental herbal medicines (TOHM) for children and adolescents with ADHD.Methods. Randomized clinical trials published from January 1, 1990, to December 31, 2010, in English, Chinese, Japanese, orKorean language which evaluated the use of TOHM on ADHD subjects of 18 years old or below, diagnosed based on DSM-IV, weresearched from MEDLINE, EMBASE, PsyINFO, Cochrane Library, and 10 other databases. Results. Twelve studies involving 1189subjects met the inclusion criteria. In general, the included studies claimed that TOHM has similar efficacy to methylphenidateand at the same time has fewer side effects compared to methylphenidate. Some studies also suggested that the effect of TOHMsustained better than methylphenidate. However, solid conclusions could not be drawn because the included studies were not ofhigh quality. Risk of bias issues such as randomization, allocation, concealment and blinding were not addressed in most of thestudies, and the risk of publication bias could not be ruled out. Conclusion. Currently, there is not strong evidence to say thatTOHM is effective in treating the core symptoms of ADHD.

1. Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a behav-ioral disorder of which patients display persistent pattern ofinattention and hyperactivity/impulsivity or a combinationof the two at an abnormal level that their social, academic, oroccupational functioning is impaired [1]. While the etiologyof ADHD is not clearly known, studies have suggested thatthe abnormality of the frontal network and dysregulationof catecholamines are the underlying pathophysiology [2].Frontal lobes are involved in decision making to convertimpulse to action, attention, and concentration, and theyare primarily activated by the catecholamines, dopamine,and norepinephrine [3]. When frontal lobes are not fullyactivated, or when there are changes in the levels of dopamineand norepinephrine, the symptoms of hyperactivity andinattention are likely.

When making a diagnosis of ADHD, clinicians shoulddetermine that the diagnostic criteria have been met byassessing information obtained from primarily parents,guardians, and teachers [4]. For adolescents, information

from at least two teachers and other sources should beassessed because adolescents usually have multiple teachersand parents have little direct contact to observe theirstrengths and problems [4, 5]. Instruments such as theRevised Conners’ Parent Rating Scale and Revised Conners’Teacher Rating Scale are useful for screening and assessingbehavioral problems, and also helpful for assessing treatmenteffectiveness [6, 7].

Behavioral therapy and pharmacotherapy are two kindsof treatments commonly used in ADHD. Recommenda-tion of treatment for ADHD varies depending on thepatient’s age. While evidence-based behavioral therapy isrecommended as the first line of treatment for preschool-aged children (4-5 years of age), school-aged children (6–11 years of age) and adolescents (12–18 years of age) arerecommended a combination of medication and behavioraltherapy [4].

Stimulants are reported to be highly effective for mostchildren in reducing the core symptoms of ADHD and thusare used as first line medication for ADHD patients [2, 4].They are structurally similar to endogenous catecholamines

2 Evidence-Based Complementary and Alternative Medicine

and are thought to work by enhancing dopaminergic andnoradrenergic neurotransmission [2, 8].

Methylphenidate (Ritalin) is the most commonly usedstimulant for the treatment of ADHD [2, 9]. Around 70%of ADHD patients who receive stimulant treatment are givenmethylphenidate [10]. It is shown to be effective, at least inshort term, on improving the core symptoms of ADHD suchas attention, distractibility, and impulsivity (effect size 0.75–0.84, mean 0.78). Methylphenidate has observable effectson improving social and classroom behavior (effect size0.63–0.85, mean 0.8) [9]. Pemoline (Cylert) is a stimulantthat is longer acting than methylphenidate, but due to itspotential for hepatotoxicity, it is regarded as a third linetreatment [2]. In some cases, nonstimulants are also used inthe treatment of ADHD such as the norepinephrine specificreuptake inhibitors atomoxetine, and antidepressants suchas Imipramine, Phenelzine, and Bupropion [2, 11] but havebeen found to have significant differences in terms of efficacycompared to stimulants [8].

While stimulants are effective for many children withADHD, they may cause side effects, with the most commonones being decreased appetite, insomnia, and headache(Cohen’s d 0.67, 0.40, and 0.33 resp.) [12]. Other side effectssuch as motor tics, abdominal pain, irritability, nausea,and fatigue are also reported [9]. Therefore, many parentsof ADHD children try to search for more natural andsafe treatment options [13, 14], which has resulted in agrowing interest in complementary and alternative therapies(CAM), such as herbal remedies, dietary supplements,dietary modification, neurofeedback, homeopathic therapy,and chiropactic, in treatment of ADHD. Several surveysconducted on the use of CAM in ADHD showed over 50%of ADHD sufferers have used CAM [13, 15].

Herbal medicine is a treatment measure used in tra-ditional Oriental medicine. Although herb usually refersto materials from plant sources, in respect of traditionalOriental medicine, herbal materials can be originated fromplants, animals, or minerals. In this review, traditionalOriental herbal medicine (TOHM) is defined as medicinemade by materials used under traditional Oriental medicaltheory. Herbal materials that are not documented in theKorean Pharmacopoeia, the Japanese Pharmacopoeia, Phar-macopoeia of the People’s Republic of China, Zhong HuaBen Cao, and Zhong Yao Da Ci Dian (Chinese Medical GreatDictionary) are considered outside the context of TOHM.TOHM should be taken orally and studies employing otherroute of administration, such as intravenous or transdermal,are excluded from this review.

Even though ADHD was not described in literatureof traditional Oriental medicine, in traditional Orientalmedical theory, ADHD is related to congenital deficiency orinsufficient postnatal nourishment that leads to imbalancesin the body. It is suggested that the disorder is related to theheart, the liver, the spleen, and the kidneys [16]. TOHM isbelieved to work by adjusting the inner imbalances of ADHDpatients and thereby relieving the symptoms.

A study on ADHD using an animal model of spon-taneous hypertensive rat treated with an Oriental herbaldecoction comprised of Caulis Polygoni Multiflori (stem

of Polygonum multiflorum Thunb.), Radix RehmanniaePreparata (processed Rehmannia root), Carapax et Plas-trum Testudinis (Carapace and plastron of Chinemys reevsii(Gray)), Os Draconis (fossilized bones), Radix Polygalae(Polygala root), and Rhizoma Acori Tatarinowii (GrassleafSweetflag Rhizome) showed that the decoction increasedthe amount of dopamine at the frontal cortex and corpusstriatum [17], suggesting that its possible mechanism inADHD is to increase dopamine level and thereby enhancecatecholaminergic neurotransmission.

This review aims to evaluate the efficacy of TOHM as atreatment for ADHD in patients under the age of 18. TOHMis natural and often perceived to have fewer side effects thanconventional ADHD pharmacotherapy. Various research andclinical studies have been conducted on TOHM’s efficacy onADHD, but very few articles review the evidence of efficacyof the treatment. A systematic review on complementarymedicines for ADHD suggested that a Chinese herbalmedicine may be effective for ADHD [18] however in thereview only one study about Chinese herbal medicine wasincluded and analyzed. Further compilation and analysis ofcurrently available data about TOHM on ADHD may help tounderstand the true effect of the treatment on the disorders,and provide insight into the direction of future research.

2. Methods

2.1. Database Searching. English, Chinese, Korean andJapanese articles on randomized clinical trials (RCTs) ofOriental herbal treatment on ADHD published betweenJanuary 1, 1990, and December 31, 2010, were searchedfrom various databases. The details of search terms usedin different databases are presented in the appendix. Thefollowing databases were searched:

(1) Cochrane Library,

(2) EMBASE,

(3) MEDLINE,

(4) AMED,

(5) CINAHL Plus,

(6) PsyINFO,

(7) SinoMed–CBM—Chinese Database,

(8) China Journal Net—Chinese Database,

(9) WanFang Data—Chinese Database,

(10) Oriental Medicine Advanced Searching IntegratedSystem (OASIS)—Korean Database,

(11) Scholarly and Academic Information Navigator(CiNii)—Japanese Database,

(12) Database of Grants-in-Aid for Scientific Research(KAKEN)—Japanese Database,

(13) Japanese Institutional Repositories Online(JAIRO)—Japanese Database,

(14) Academic Research Database Repository (NII-DBR)—Japanese Database.

Evidence-Based Complementary and Alternative Medicine 3

2.2. Reference List. Other than searching from databases, thereference lists of the included studies were referred to in orderto identify more potential articles.

2.3. Criteria for Considering Studies for This Review

2.3.1. Type of Studies. Randomized clinical trials of TOHM.The efficacy of TOHM treatment should be compared toeither a placebo or a conventional medication used fortreating ADHD. If there was a baseline treatment, it had to bethe same in both the treatment and control groups. Studiesonly comparing different TOHM formulae, or comparingTOHM with other traditional Oriental treatment such asacupuncture were excluded. Studies without indicating “ran-domized” were considered not randomized and excluded.

2.3.2. Type of Participants. Subjects under the age of 18 whowere diagnosed with ADHD based on DSM-IV.

2.3.3. Type of Interventions. Traditional Oriental herbalmedicine must be used. Herbs that are not documented inthe Korean Pharmacopoeia, the Japanese Pharmacopoeia,Pharmacopoeia of the People’s Republic of China, ZhonghuaBencao, and Zhongyao Dacidian were not considered. Othertreatment measures of Oriental medicines such as acupunc-ture and moxibustion were excluded.

2.3.4. Types of Outcome Measures. The core symptoms ofADHD (hyperactivity, impulsivity, and inattention) wereconsidered in this review. Core symptoms should be assessedby at least one of the following tools: Revised Conners’ ParentRating Scale, Revised Conners’ Teacher Rating Scale, Con-ners’ Hyperactivity Index, Conners’ Abbreviated SymptomsQuestionnaire, Conners’ Global Index for Parents, and/orConners’ Global Index for Teachers.

2.4. Risk of Bias Assessment of Included Studies. The risk ofbias of all the included studies was assessed according toCochrane Handbook for Systematic Reviews of Inventionversion 5.1.0.

3. Results

The search came up with 1240 results, and 12 studies [16, 19–29] involving 1189 subjects were included in this review (seeFigure 1 for included studies selection).

All of the studies included in this review were conductedin China as single-centre trials. Five results in Japanese andeighteen results in Korean were identified. Only one Japanesearticle was about a clinical trial; however the trial was not arandomized trial and was therefore not selected.

Among the twelve included studies, none included theinformation on how sample size was derived and whetherthe study was statistically powered. The length of studyranged from 4 weeks to 24 weeks. Six studies had follow-up observation on subjects, ranging from 2 weeks to12 months after finishing treatment, to evaluate whetherthe intervention sustained effectiveness after treatment is

stopped while the other six studies did not report iffollow-up observations were conducted. Ten of the includedstudies reported homogeneity of baseline characteristics, butonly seven [20, 22, 24, 26–29] showed relevant descriptivestatistical data. Two studies [16, 19] did not report if baselinecharacteristics of subjects were homogenous. Only one ofthe studies [27] specified the subtype of ADHD subjectsincluded in the study. Characteristics of included studies aresummarized in Table 1.

3.1. Assessment of Risk of Bias. In general, the risk of bias inthe included articles is unclear. Very limited information wasrevealed in the studies to enable the reviewers to tell if theincluded studies were at risk of bias.

Only one of the included studies [16] described how ran-domization was done, but the study used two randomizationmethods where part of the subjects were randomized usinga random number table while part were allocated to thetreatment or control groups by their patient record numbers.The allocation concealment issue was not addressed in any ofthe included studies.

The blinding method was also not addressed in mostof the studies, and only two of the included studies [22,26] claimed to be a double-blind trial. Li et al. (1999)described the blinding method, which was to include aplacebo resembling methylphenidate in the treatment groupand a placebo that looked like the corresponding TOHM inthe control group. Wang et al. (2003) did not describe howblinding was done.

Most of the studies indicated no missing data. However,Ma et al. (2007) [25] did not specify the initial numberof subjects so it could not be determined if there was anyparticipant drop-out. Ma et al. (2007) [16] reported sevendrop-outs but no explanations were provided, and it wasunclear whether the drop-outs were from the treatmentgroup or the control group. In another study [23], threesubjects were excluded and there were five drop-outs, but thereasons were not sufficiently provided. Among those eightsubjects, it is only known that four of the drop-outs werereported to have terminated the study due to adverse effectof methylphenidate. Those three studies were considered tohave unknown risk of bias on incomplete outcome data.

Study protocols were not available for any of the includedstudies, therefore it could not be discerned whether all pre-specified outcomes were reported. Lai and Li (2006) [21] didnot report the baseline score before treatment and score aftertreatment. Xu (2005) [27] did not report the baseline scoreof rating. The two studies were considered to have high riskof reporting bias.

The risk of bias graph and summary are presented inFigures 2 and 3, respectively.

3.2. Diagnosis and Assessment of the Disorder. Although allincluded studies specified the diagnostic criteria and methodto assess treatment effect, only one study [16] specifiedwho completed the rating questionnaire or did the ratingassessment. None of the studies addressed under whichsetting the assessment was done. Also, the language of


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iou

sim

prov

emen

tin

stu

dyin

g,eff

ecti

ven

ess

sust

ain

saf

ter

stop

pin

gm

edic

atio

nfo

r6

mon

ths,

Ch

ines

em

edic

ine

ther

apeu

tic

inde

x≥9

0%:

trea

tmen

t/co

ntr

ol:6

/2(i

i)Sh

owin

geff

ecti

ven

ess—

obvi

ous

alle

viat

ion

ofco

resy

mpt

oms,

Con

ner

sin

dex

decr

ease≤8

0%an

d>

50%

,im

prov

emen

tin

stu

dyin

g,C

hin

ese

med

icin

eth

erap

euti

cin

dex<

90%

and≥6

0%:t

reat

men

t/co

ntr

ol:2

0/18

(iii)

Show

ing

impr

ovem

ent—

impr

ovem

ent

ofco

resy

mpt

oms,

Con

ner

sin

dex

decr

ease≤5

0%an

d>

30%

,im

prov

emen

tin

stu

dyin

gbu

tn

otst

able

,Ch

ines

em

edic

ine

ther

apeu

tic

inde

x<

60%

and≥1

0%:

trea

tmen

t/co

ntr

ol:2

6/22

(iv)

Ineff

ecti

ve—

no

impr

ovem

ent

orw

orse

nin

gin

core

sym

ptom

san

dst

udy

ing,

Con

ner

sin

dex

decr

ease≤3

0%,

Ch

ines

em

edic

ine

ther

apeu

tic

inde

x<

10%

:tr

eatm

ent/

con

trol

:6/6


Ta

ble

1:C

onti

nu

ed.

Stu

dyM

eth

odPa

rtic

ipan

tsIn

terv

enti

onO

utc

omes

Lin

etal

.200

7[2

4]R

ando

miz

edC

ontr

olTr

ial

Trea

tmen

tgro

upN

um

ber:

40,m

ale/

fem

ale:

32/8

Age

ran

ge:6

.5–1

3,m

ean

8.7±

2.7

Con

trol

grou

p1

(Rit

alin

)N

um

ber:

40,m

ale/

fem

ale:

31/9

Age

ran

ge:7

–12,

mea

n8.

5±

2.5

Con

trol

grou

p2

(tre

atm

ent

+R

ital

in)

Nu

mbe

r:40

,mal

e/fe

mal

e:32

/8A

gera

nge

:7–1

1,m

ean

8.2±

2.1

Cou

ntr

y:C

hin

aD

iagn

osti

ccr

iter

ia:D

SM-I

VB

asel

ine

char

acte

rist

ic:H

omog

enei

tyfo

rge

nde

r,ag

e,an

dco

urs

eof

dise

ase

Trea

tmen

tgro

upN

ings

hen

oral

liqu

id30

–60

mL

per

day

for

12w

eeks

Con

trol

grou

p1

Rit

alin

5m

g–40

mg

per

day

for

12w

eeks

Con

trol

grou

p2

Nin

gsh

enor

alliq

uid

30–6

0m

Lpl

us

Rit

alin

5m

g–40

mg

per

day

for

12w

eeks

Th

est

udy

defi

ned

trea

tmen

teff

ect

asfo

llow

s:(i

)N

ear

reco

very

—di

sapp

eara

nce

ofco

resy

mpt

oms,

Con

ner

sin

dex

decr

ease

>80

%,o

bvio

us

impr

ovem

ent

inst

udy

ing:

trea

tmen

t/co

ntr

ol1/

con

trol

2:4/

3/7

(ii)

Show

ing

effec

tive

nes

s—ob

viou

sal

levi

atio

nof

core

sym

ptom

s,C

onn

ers

inde

xde

crea

se≤8

0%an

d>

50%

,im

prov

emen

tin

stu

dyin

g:tr

eatm

ent/

con

trol

1/co

ntr

ol2:

7/7/

10(i

ii)Sh

owin

gim

prov

emen

t—im

prov

emen

tof

core

sym

ptom

s,C

onn

ers

inde

xde

crea

se≤5

0%an

d>

30%

,im

prov

emen

tin

stu

dyin

gbu

tn

otst

able

:tr

eatm

ent/

con

trol

1/co

ntr

ol2:

16/1

9/17

(iv)

Ineff

ecti

ve—

no

impr

ovem

ent

orw

orse

nin

gin

core

sym

ptom

san

dst

udy

ing,

Con

ner

sin

dex

decr

ease≤3

0%:

trea

tmen

t/co

ntr

ol1/

con

trol

2:13

/11/

6

Ass

essm

ent

ofC

onn

ers

inde

x12

wee

ksaf

ter

stop

pin

gm

edic

atio

nre

port

edth

atth

ere

was

sign

ifica

nt

drop

ineff

ecti

ven

ess

inR

ital

inco

ntr

olgr

oup

but

not

intr

eatm

ent

grou

pan

dco

mbi

ned

trea

tmen

tgr

oup.

Ma

2007

[16]

Ran

dom

ized

Con

trol

Tria

l

Trea

tmen

tgro

upN

um

ber:

22,m

ale/

fem

ale:

15/7

Con

trol

grou

pN

um

ber:

20,m

ale/

fem

ale:

20/1

6

Age

ran

ge:6

–13

Cou

ntr

y:C

hin

aD

iagn

osti

ccr

iter

ia:D

SM-I

VB

asel

ine

char

acte

rist

ic:n

otde

scri

bed

Th

ere

wer

eor

igin

ally

49su

bjec

tsin

the

stu

dyan

d7

case

sw

ere

attr

ited

,bu

tth

ere

was

no

indi

cati

onof

wh

eth

erth

eybe

lon

ged

totr

eatm

ent

grou

pan

dco

ntr

olgr

oup.

Rea

son

sfo

rat

trit

ion

wer

eal

son

otsu

ffici

entl

ypr

esen

ted

Trea

tmen

tgro

upD

uod

ongt

ing

deco

ctio

n15

0m

Lea

chti

me

for

age

4–7,

200

mL

each

tim

efo

rag

e8–

12,

twic

ea

day

for

28da

ys,a

nd

brea

kfo

r2

days

(1tr

eatm

ent

cycl

e)be

fore

star

tin

gan

oth

ertr

eatm

ent

cycl

e,fo

r2

cycl

es+

beh

avio

ral

ther

apy

Con

trol

grou

pR

ital

in0.

45m

g/kg

for

28da

ysan

dbr

eak

for

2da

ys(1

trea

tmen

tcy

cle)

befo

rest

arti

ng

anot

her

trea

tmen

tcy

cle,

for

2cy

cles

+be

hav

iora

lth

erap

y

Th

est

udy

defi

ned

trea

tmen

teff

ect

asfo

llow

s:(i

)Sh

owin

geff

ecti

ven

ess—

hype

ract

ivit

y,an

din

atte

nti

onal

levi

ated

by2/

3:tr

eatm

ent/

con

trol

:7/6

(ii)

Show

ing

impr

ovem

ent—

obvi

ous

sym

ptom

atic

impr

ovem

ent,

hype

ract

ivit

yan

din

atte

nti

onal

levi

ated

by1/

2:tr

eatm

ent/

con

trol

:11/

10(i

ii)

Ineff

ecti

ve—

no

sym

ptom

atic

relie

faft

er2

trea

tmen

tcy

cles

trea

tmen

t/co

ntr

ol:4

/4


Ta

ble

1:C

onti

nu

ed.

Stu

dyM

eth

odPa

rtic

ipan

tsIn

terv

enti

onO

utc

omes

Ma

etal

.200

7[2

5]R

ando

miz

edC

ontr

olTr

ial

Trea

tmen

tgr

oup/

con

trol

grou

p-C

hin

ese

med

icin

e/co

ntr

olgr

oup-

Rit

alin

:55/

53/5

1

Cou

ntr

y:C

hin

aD

iagn

osti

ccr

iter

ia:D

SM-I

VB

asel

ine

char

acte

rist

ic:h

omog

enei

tyfo

rag

e,ge

nde

r,an

dco

urs

eof

dise

ase

Att

riti

oncr

iter

iaw

asm

enti

oned

but

ther

ew

asn

oin

dica

tion

ifan

ysu

bjec

tw

asat

trit

edbe

cau

sein

itia

lnu

mbe

rof

subj

ects

ran

dom

ized

was

not

stat

ed

Trea

tmen

tgro

upY

Izh

inin

gsh

engr

anu

les

10g

each

tim

efo

rag

e6–

10,1

5g

each

tim

efo

rag

e11

–18,

twic

ea

day

for

24w

eeks

Con

trol

grou

p1-

Chi

nese

med

icin

eJi

ngn

ing

oral

liqu

id10

mL

each

tim

e,tw

ice

ada

y,5

days

per

wee

kfo

r24

wee

ks

Con

trol

grou

p2-

Rit

alin

Rit

alin

5m

gea

chti

me

for

age

6–8,

and

10m

gea

chti

me

for

age

9–18

,tw

ice

ada

y,5

days

per

wee

kfo

r24

wee

ks

Th

est

udy

defi

ned

trea

tmen

teff

ect

asfo

llow

s:(i

)R

ecov

ery—

disa

ppea

ran

ceof

core

sym

ptom

s,C

onn

ers

inde

xde

crea

se>

80%

,obv

iou

sim

prov

emen

tin

stu

dyin

gan

dso

cial

fun

ctio

n,C

hin

ese

med

icin

eth

erap

euti

cin

dex

≥90%

:tre

atm

ent/

con

trol

1/co

ntr

ol2:

6/3/

3(i

i)Sh

owin

geff

ecti

ven

ess—

obvi

ous

alle

viat

ion

ofco

resy

mpt

oms,

Con

ner

sin

dex

decr

ease≤8

0%an

d>

50%

,im

prov

emen

tin

stu

dyin

gan

dso

cial

fun

ctio

n,C

hin

ese

med

icin

eth

erap

euti

cin

dex<

90%

and≥6

0%:

trea

tmen

t/co

ntr

ol1/

con

trol

2:29

/18/

19(i

ii)Sh

owin

gim

prov

emen

t—im

prov

emen

tof

core

sym

ptom

s,C

onn

ers

inde

xde

crea

se≤5

0%an

d>

30%

,im

prov

emen

tin

stu

dyin

gbu

tn

otst

able

,Ch

ines

em

edic

ine

ther

apeu

tic

inde

x<

60%

and≥1

0%:

trea

tmen

t/co

ntr

ol1/

con

trol

2:15

/27/

22(i

v)In

effec

tive

—n

oim

prov

emen

tor

wor

sen

ing

inco

resy

mpt

oms

and

stu

dyin

g,C

onn

ers

inde

xde

crea

se≤3

0%,

Ch

ines

em

edic

ine

ther

apeu

tic

inde

x<

10%

:tr

eatm

ent/

con

trol

1/co

ntr

ol2:

5/5/

7

Wan

gan

dSh

i20

03[2

6]R

ando

miz

edC

ontr

olTr

ial

Trea

tmen

tgro

upN

um

ber:

58,m

ale/

fem

ale:

49/9

Age

ran

ge:m

ean

9.3±

2.9

Con

trol

grou

pN

um

ber:

50,m

ale/

fem

ale:

42/8

Age

ran

ge:m

ean

9.5±

3.2

Cou

ntr

y:C

hin

aD

iagn

osti

ccr

iter

ia:D

SM-I

Van

dC

onn

ers

inde

x>

1.5

Bas

elin

ech

arac

teri

stic

:hom

ogen

eity

for

age,

gen

der,

cou

rse

ofdi

seas

e,an

dIQ

Trea

tmen

tgro

upJi

ngn

ing

oral

liqu

id10

mL

each

tim

e,tw

ice

ada

yfo

r4

wee

ks

Con

trol

grou

pR

ital

in10

mg

inth

em

orn

ing

and

5m

gat

nig

ht

for

4w

eeks

Th

est

udy

defi

ned

trea

tmen

teff

ect

asfo

llow

s:(i

)Sh

owin

geff

ecti

ven

ess—

disa

ppea

ran

ceof

sym

ptom

s,ob

viou

sim

prov

emen

tin

soci

alfu

nct

ion

and

stu

dyin

g,C

onn

ers

inde

x<

1.2:

trea

tmen

t/co

ntr

ol:2

7/23

(ii)

Show

ing

impr

ovem

ent—

impr

ovem

ent

ofsy

mpt

oms,

impr

ovem

ent

inso

cial

fun

ctio

nan

dst

udy

ing

but

impr

ovem

ent

not

stab

le,d

ecre

ase

inC

onn

ers

inde

xbu

tst

ill>

1.5:

trea

tmen

t/co

ntr

ol:2

6/22

(iii

)In

effec

tive

—n

oim

prov

emen

tor

wor

sen

ing

insy

mpt

oms,

Con

ner

sin

dex

and

stu

dyin

g:tr

eatm

ent/

con

trol

:5/5

No

side

effec

tsob

serv

edin

trea

tmen

tgr

oup

but

10su

bjec

tsin

con

trol

grou

pre

port

edn

ause

aan

dlo

ssin

appe

tite

,2su

bjec

tsre

port

eddi

zzin

ess,

and

1su

bjec

tre

port

edsl

eepl

essn

ess.


Ta

ble

1:C

onti

nu

ed.

Stu

dyM

eth

odPa

rtic

ipan

tsIn

terv

enti

onO

utc

omes

Xu

2005

[27]

Ran

dom

ized

Con

trol

Tria

l

Trea

tmen

tgro

upN

um

ber:

100,

mal

e/fe

mal

e:87

/13

Age

ran

ge:m

ean

9.3±

2.4

Con

trol

grou

pN

um

ber:

50,m

ale/

fem

ale:

43/7

Age

ran

ge:m

ean

9.1±

2.3

Cou

ntr

y:C

hin

aD

iagn

osti

ccr

iter

ia:D

SM-I

Vcr

iter

iaof

com

bin

edty

pe

AD

HD

Bas

elin

ech

arac

teri

stic

:hom

ogen

eity

for

age,

gen

der,

cou

rse

ofdi

seas

e,an

dIQ

Trea

tmen

tgro

upJi

ngn

ingz

hid

ong

gran

ule

s1

g/kg

/day

,m

axim

um

50g,

for

12w

eeks

Con

trol

grou

pR

ital

in0.

3m

g/kg

/day

,in

crea

sedo

sage

grad

ual

lyto

max

imu

m0.

6m

g/kg

/day

,for

12w

eeks

Th

est

udy

defi

ned

trea

tmen

teff

ect

asfo

llow

s:(i

)Sh

owin

geff

ecti

ven

ess—

decr

ease

inC

onn

ers

inde

xby

≥66%

:tre

atm

ent/

con

trol

:56/

26(i

i)Sh

owin

gim

prov

emen

t—de

crea

sein

Con

ner

sin

dex

≥33%

and<

66%

:tre

atm

ent/

con

trol

:22/

14(i

ii)

Ineff

ecti

ve—

decr

ease

inC

onn

ers

inde

x<

33%

:tr

eatm

ent/

con

trol

:22/

10

Th

ere

was

alm

ost

no

side

effec

tre

port

edin

trea

tmen

tgr

oup

but

subj

ects

inco

ntr

olgr

oup

repo

rted

mor

eob

viou

san

dpe

rsis

ten

tsi

deeff

ects

.Ass

essm

ent

ofC

onn

ers

inde

x4

wee

ksaf

ter

stop

pin

gm

edic

atio

nre

port

edth

atth

ere

was

sign

ifica

nt

drop

ineff

ecti

ven

ess

inco

ntr

olgr

oup

but

not

intr

eatm

ent

grou

p.

L.Ya

ng

and

J.Ya

ng

2005

[28]

Ran

dom

ized

Con

trol

Tria

l

Trea

tmen

tgro

upN

um

ber:

48,m

ale/

fem

ale:

40/8

Age

ran

ge:6

–12

(mea

n8.

3)

Con

trol

grou

pN

um

ber:

38,m

ale/

fem

ale:

31/7

Age

ran

ge:6

.5–1

3(m

ean

8.6)

Cou

ntr

y:C

hin

aD

iagn

osti

ccr

iter

ia:D

SM-I

VB

asel

ine

char

acte

rist

ic:H

omog

enei

tyfo

rge

nde

r,ag

e,co

urs

eof

dise

ase,

and

coex

isti

ng

sym

ptom

s

Trea

tmen

tgro

upY

izh

inin

gsh

enor

alliq

uid

2×

10m

L,3

tim

esa

day

for

3m

onth

s+

beh

avio

ralt

her

apy

Con

trol

grou

pR

ital

in10

mg,

once

per

day

for

3m

onth

s,n

om

edic

atio

ndu

rin

gw

eeke

nd

and

hol

iday

+be

hav

iora

lth

erap

y

Th

est

udy

defi

ned

trea

tmen

teff

ect

asfo

llow

s:(i

)R

ecov

ery—

disa

ppea

ran

ceof

core

sym

ptom

s,C

onn

ers

inde

xde

crea

se>

80%

,obv

iou

sim

prov

emen

tin

stu

dyin

g,eff

ecti

ven

ess

sust

ain

saf

ter

stop

pin

gm

edic

atio

nfo

r6

mon

ths:

trea

tmen

t/co

ntr

ol:6

/2(i

i)Sh

owin

geff

ecti

ven

ess—

obvi

ous

alle

viat

ion

ofco

resy

mpt

oms,

Con

ner

sin

dex

decr

ease

>50

%,i

mpr

ovem

ent

inst

udy

ing:

trea

tmen

t/co

ntr

ol:1

6/15

(iii)

Show

ing

impr

ovem

ent—

impr

ovem

ent

ofco

resy

mpt

oms,

Con

ner

sin

dex

decr

ease

>30

%,i

mpr

ovem

ent

inst

udy

ing

but

not

stab

le:t

reat

men

t/co

ntr

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Record identified through

database searching

N = 1235

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N = 5

After duplicates removed

N = 790

Record screened

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for eligibility

N = 124

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qualitative synthesis

N = 12

666 records excluded

Reasons:

• Irrelevant topic• Review/case report• Animal study

112 records excluded

Reasons:

• Not controlled or randomized trial• Improper control group• Improper diagnostic/assessment criteria

• Combined other treatments/differentbaseline treatment

Figure 1: Selection of studies flowchart.

Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting bias)

Other bias

0 25 50 75 100

(%)

Low risk of biasUnclear risk of biasHigh risk of bias

Figure 2: Risk of bias graph of the included studies.


Cheng et al. 2006

Kong et al. 2007

L. Yang and J.Yang 2005

Lai and Chen 1999

Lai and Li 2006

Li et al. 2004

Lin et al. 2007

Ma et al. 2007

Ma 2007

Wang and Shi 2003

Xu et al. 2005

Yu and Wang 2005

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assessment tools was not specified. It was not clear if theassessment tools were validated in cases where they weretranslated into another language.

3.3. Treatment Effectiveness. The herbal formulae used inthe included twelve studies varied, and dosage forms ofdecoction, granules, oral liquids, pill, and so forth were used.Nine studies [16, 19–22, 25, 27–29] provided the ingredientsof the formulae, but among them five [22, 25, 27–29] didnot specify the amount of each herb used in the formula,and therefore there was very little information on drug toextract ratio. Three studies [23, 24, 26] did not provide theformula at all. None of the studies mentioned how the herbalmedicines used were standardized. The details of the herbalingredients used in the included studies, their dosage form,and daily dose are presented in Table 2.

Among the twelve studies, there were ten 2-arm studies[16, 19–23, 26–29] that compared the effectiveness ofTOHM to methylphenidate, and one 3-arm study [24] whichincluded a TOHM treatment group, a TOHM control group,and methylphenidate control group. These studies claimedthat TOHM had no significant difference on effectivenesscompared to methylphenidate. However, seven of them[16, 21, 22, 26–29] did not conduct statistical analyses todemonstrate whether there was significant efficacy comparedto the baseline.

The remaining one of the twelve included studies [24]evaluated the net effect of TOHM by having a combinedtreatment group of TOHM and methylphenidate, and amethylphenidate control group. The study reported thatTOHM and methylphenidate worked better in combinationthan methylphenidate alone, with statistically significantdifferences when comparing the rate of effectiveness of thetwo groups.

3.4. Follow-Up Observation on Effectiveness. Among theincluded studies, six had follow-up observations to evaluatethe sustainability of treatment effect of core symptom afterstopping medication, while the other six studies did notspecify if follow-up observation was done. The follow-upperiod varied from 2 weeks to 12 months after stopping thetreatment. For the six studies with follow-up observation,five [20, 23, 24, 27, 28] compared the treatment effect ofTOHM and methylphenidate after stopping medication andall reported the effect of TOHM sustained better comparedto methylphenidate. The remaining one [25] only followedup on the effect of the TOHM treatment group.

3.5. Safety and Side Effects. In general, TOHM was claimedto have fewer side effects than methylphenidate. Eight ofthe included studies [19–24, 27, 28] discussed side effects.In general, more cases of side effect were reported in themethylphenidate control group than the TOHM treatmentgroup. Two studies [26, 28] reported no cases of sideeffect in the TOHM treatment group. Cheng et al. (2006)reported that among the side effect cases in their study, drymouth, sweating, nausea, weight loss, loss of appetite, andheadache were significantly fewer in the TOHM treatmentgroup compared to the methylphenidate control group(P < 0.05) [19]. Lai and Li (2006) reported that casesof loss of appetite and drowsiness were significantly fewer(P < 0.05) [21]. Lin et al. (2007) reported that casesof sleeplessness, dizziness/headache, sweating, dry mouth,nausea, loss of appetite, weight loss, and constipation weresignificantly fewer in the treatment group than the controlgroup (P < 0.01) [24]. Xu (2005) compared the averagescore of Treatment Emergent Symptoms Scale (TESS) in thetreatment group and the control group, and reported that theaverage score was significantly higher in the control group(P < 0.01) [27]. Four other studies [19, 20, 22, 26] alsoclaimed to have used TESS to evaluate side effects but scoreswere not reported.

Three studies [16, 25, 28] performed liver function tests,renal function tests, and/or ECGs on subjects after treatment


Table 2: Details of the herbal treatments used in the included studies.

Cheng et al. 2006[19]

Ingredients and amount: Radix Rehmanniae Preparata 6 g, Carapax et Plastrum Testudinis 5 g, Cervi CornuDegelatinatum 5 g, Rhizoma Acori Tatarinowii 10 g, Radix Polygalae 10 g, Radix et Rhizoma Salviae Miltiorrhizae10 g, Fructus Schisandrae Chinensis 5 gDosage form: Decoction. The above amount of ingredients are boiled with water to yield 90 mL of decoction.Daily dose: 90 mLStandardization: not known

Kong et al. 2007[20]

Ingredients and amount: Fructus Lycii 9 g, Flos Chrysanthemi 9 g, Radix Rehmanniae Preparata 24 g, Fructus Corni12 g, Rhizoma Dioscoreae 12 g, Rhizoma Alismatis 9 g, Cortex Moutan 9 g, Poria 9 gDosage form: Pills. It was not clear how many pills were made out of the above amount of herbs.Daily dose: 9 pillsDrug to extract ratio: not knownStandardization: not known

Lai and Li 2006[21]

Ingredients and amount: Os Draconis 20 g, Carapax et Plastrum Testudinis 10 g, Radix Polygalae 5 g, Rhizoma AcoriTatarinowii 10 g, Fructus Tritici Levis 20 g, Radix Ophiopogonis 10 g, Caulis Polygoni Multiflori 15 g, RadixCodonopsis 15 g, Poria 15 g, Radix Rehmanniae Preparata 15 g, Fructus Schisandrae Chinensis 4 g, Radix et RhizomaGlycyrrhizae 4 g. Depending on the symptoms of different patients, other herbs might be added but the amount wasnot specified.Dosage form: Decoction. 150 mL of decoction was made from the above ingredients.Daily dose: 150 mLStandardization: not known

Li and Chen 1999[22]

Ingredients and amount: Fructus Lycii, Radix Rehmanniae Preparata, Fructus Schisandrae Chinensis, Radix etRhizoma Ginseng, Poria, Radix et Rhizoma Glycyrrhizae. Amount was not specified.Dosage form: GranulesDaily dose: 3 g or 6 g depending on the age of subjectDrug to extract ratio: not knownStandardization: not known

Li et al. 2004 [23]

Ingredients and amount: not knownDosage form: GranulesDaily dose: 2 doses or 4 doses depending on the age of subject. Amount of granules contained in 1 dose was notspecified.Drug to extract ratio: not knownStandardization: not known

Lin et al. 2007 [24]

Ingredients and amount: not knownDosage form: oral liquidDaily dose: 30–60 mLDrug to extract ratio: not knownStandardization: not known

Ma 2007 [16]

Ingredients and amount: Flos Magnoliae 10 g, Radix Paeoniae Alba (parched) 30 g, Rhizoma Gastrodiae 8 g, RadixIsatidis 15 g, Radix Scrophulariae 15 g, Massa Medicata Fermentata 6 g, Fructus Crataegi 6 gDosage form: Decoction. The amount of decoction yielded from the above ingredients was not specified.Daily dose: 150 mL or 200 mL depending on the age of subjectDrug to extract ratio: not knownStandardization: not known

Ma et al. 2007 [25]

Ingredients and amount: Homonis Placenta, Radix Rehmanniae Preparata, Rhizoma Acori Tatarinowii, RadixPolygalae, Rhizoma Alismatis, Rhizoma Coptidis, and so forth. Amount was not specified.Dosage form: GranulesDaily dose: 20 g or 30 g depending on the age of subjectDrug to extract ratio: not knownStandardization: not known

Wang and Shi 2003[26]

Ingredients and amount: not knownDosage form: Oral liquidDaily dose: 20 mLDrug to extract ratio: not knownStandardization: not known

Xu 2005 [27]

Ingredients and amount: Radix Bupleuri, Radix Peoniae Alba, Ramulus cum Uncis Uncariae, Os Draconis,Margaritifera Concha, Radix Pseudostellariae, Fructus Alpiniae Oxyphyllae, Radix Polygalae, Rhizoma AcoriTatarinowii, Fructus Schisandrae Chinensis, Poria, Radix et Rhizoma Glycyrrhizae Preparata. Amount was notspecified.Dosage form: Granules. 1 g of granules is equivalent to 5 g of herbs.Daily dose: up to 50 g depending on the body weight of subjectStandardization: not known


Table 2: Continued.

L. Yang and J. Yang2005 [28]

Ingredients and amount: Radix Rehmanniae Preparata, Radix Astragali, Radix Peoniae Alba, Os Draconis, RadixPolygalae, Rhizoma Acori Tatarinowii, Fructus Schisandrae Chinensis, Rhizoma Atractylodis Macrocephalae.Amount not specified.Dosage form: Oral liquidDaily dose: 60 mLStandardization: not known

Yu and Wang 2005[29]

Ingredients and amount: Rhizoma Coptidis, Pericarpium Citri Reticulatae, Rhizoma Pinelliae Preparatum, Poria,Rhizoma Atractylodis Macrocephalae, Radix Peoniae Alba, Ramulus cum Uncis Uncariae, Flos Chrysanthemi, RadixPolygalae, Fructus Alpiniae Oxyphyllae, Fructus Corni. Amount was not specified. Other herbs might be addeddepending on the symptoms of individual subject but the exact ingredients and amount were not given.Dosage form: DecoctionDaily dose: 1 dose. The amount of 1 dose was not specified.Drug to extract ratio: not knownStandardization: not known

and results showed that subjects had no impairment onliver function, renal function, and/or cardiac function aftertreatment with TOHM and methylphenidate, suggestingthat both TOHM and methylphenidate do not cause anysignificant safety concern on treatment of ADHD, at least inthe short term.

4. Discussion

This review included twelve studies, and though findings ofthis review suggested that the herbal preparations coveredunder the term TOHM may be effective in treating thecore symptoms of ADHD; the overall evidence is not strongenough to draw solid conclusions, because in general theclinical trials were not of high quality and the herbalpreparations far too different. Additionally, it cannot be ruledout that there is possibility of publication bias.

The included studies that discussed side effect issues allsuggested that TOHM had fewer side effects compared tomethylphenidate. However, such result should be interpretedwith caution, because first of all it was not clear whetherthe side effect cases, both in the TOHM group and themethylphenidate group, were investigated to find out ifthey were related to the intervention. Secondly, it wasnot addressed in most studies whether blinding was done.As mentioned, since TOHM is indigenous to the studypopulation, and is often perceived as natural with fewer sideeffects, if measures are not properly done to blind subjectsfrom knowing what treatment they are getting, it may causebias in reporting side effects.

In the future, should more clinical trials on ADHD usingTOHM as treatment be conducted, clinical investigatorsshould consider to address the issues discussed below inorder to improve the robustness of data.

In the diagnosis of ADHD and assessment of treatmentefficacy, tools such as rating scales are often used. In orderto make precise assessment, information should be obtainedfrom different parties including parents, guardians, andteachers under different settings, such as home and school[4]. However, among the included studies, eleven of them didnot specify who completed the questionnaires for assessmentor under which setting the assessment was done. It was

difficult to tell whether sufficient information was obtainedto facilitate an accurate assessment of the treatment effect.Also, since the studies were done in Chinese population, itwas possible the questionnaires used were in Chinese, but noinformation was available to tell whether the questionnaires,in case written in another language, were validated or not.Investigators did not indicate whether the tool of assessmenthas been modified to suit the study purpose as well. Suchinformation should be described in the study methods.

Among the included studies, the herbal medicines them-selves varied. Some of the studies did not tell what herbswere used, some did not specify the amount of herbs used,and the treatment dosage was not clear in some studies.Also, the treatment period varied for each study. Due tosuch heterogeneity, it is not possible to deduce from the datawhich herbal formulae or ingredients may be effective forADHD, nor to conclude that TOHM is effective for ADHDin children and adolescents. Although it is inevitable thatdifferent studies may use different herbs and have differenttreatment periods, the materials used and the amount shouldbe stated clearly in the publication of clinical trial results. Asvarious herbal treatments are used in different clinical studiesthe results even of the positive studies cannot be compared.Clinical investigators may have to consider repeating a studywith the same herbal treatment, or to conduct a clinical trialin multiple sites.

Due to the complex nature of herbs, how the consistencyof herbal treatment is maintained throughout a clinicalstudy is often an issue to consider. Most of the studiesincluded in this review used the herbal treatment substancesin form of decoctions or other preparations such as granulesor oral liquid prepared by the clinical sites. It was notaddressed how the consistency of treatment substances waskept throughout the studies, or how the treatment substanceswere standardized to ensure quality. In addition, in threeof the studies [16, 21, 29], prescriptions given to subjectsvaried according to their symptoms. Although one of thecharacteristics of traditional Oriental medicine is tailor-made treatment according to the patient’s condition, ina clinical study setting, this may introduce confoundingvariables. Investigators should make an effort to ensure theherbal treatment used in a study is of consistent quality


throughout the study period. One of the possible ways toaddress this problem is to use herbal medicines prepared byqualified pharmaceutical manufacturers, and the treatmentpreparation should also be standardized.

4.1. Strength of This Review . In this review, the reviewersperformed a thorough search in various databases. Otherthan major databases that have information of articlespublished mostly in English, additional Chinese, Korean,and Japanese databases were searched to identify potentialstudies. Articles written in English, Chinese, Korean, andJapanese languages were screened in order to include as manysuitable studies in the review as possible.

4.2. Limitation of This Review. Due to limited resources,the reviewers could only seek published studies. For a robustreview, nonpublished data should also be sought. Also, thereviewers were not able to contact the authors of includedstudies for clarification and further information on theirstudies.

Even though the reviewers did a thorough search ofpublished studies, the included studies were all conducted onChinese population. Little could be told about the effect ofTOHM on ADHD on populations of other countries .

5. Conclusion

This review included twelve studies on different herbalpreparations from TOHM as a treatment for children andadolescents with ADHD. Findings suggest that some of themmay have similar efficacy to methylphenidate, but solidconclusions could not be drawn due to quality problems ofthe clinical trials. In conclusion, currently there is no strongevidence to suggest that TOHM is effective in treating thecore symptoms of ADHD. More studies with low risk of biasand using the same herbal preparation are required beforefurther conclusions can be drawn.

Appendix

Search Terms Used in Different Databases

Cochrane Library, EMBASE, MEDLINE, AMED, CINAHLPlus, PsyINFO. ADHD (or attention-deficit/hyperactivitydisorder or hyperkinetic disorder or minimal brain dysfunc-tion) and alternative medicine (or complementary medicineor Chinese medicine or kampo or Korean medicine orOriental medicine or phytotherapy or herbal).

SinoMed (CBM), China Journal Net, WanFang Data—

Chinese Databases

(1) ADHD and Chinese medicine (in Chinese).

(2) Attention-deficit/hyperactivity disorder (in Chinese)and Chinese medicine (in Chinese).

(3) Hyperactivity (in Chinese) and Chinese medicine (inChinese).

(4) Minimal brain dysfunction (in Chinese) and Chinesemedicine (in Chinese).

(5) Hyperkinetic disorder (in Chinese) and Chinesemedicine (in Chinese).

Oriental Medicine Advanced Searching Integrated System

(OASIS)—Korean Database

(1) ADHD.

(2) Attention-deficit/hyperactivity disorder (in Korean).

Scholarly and Academic Information Navigator (CiNii),

Database of Grants-in-Aid for Scientific Research (KAKEN),

Japanese Institutional Repositories Online (JAIRO), Aca-

demic Research Database Repository (NII-DBR)—Japanese

Databases

(1) ADHD and Kampo (in Japanese).

(2) Attention-deficit/hyperactivity disorder (in Japanese)and Kampo (in Japanese).

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TraditionalOrientalHerbalMedicineforChildrenand ...2.3. Criteria for Considering Studies for This Review 2.3.1. Type of Studies. Randomized clinical trials of TOHM. The eﬃcacy of