Review Article Natural Product-Derived Treatments for ...downloads.hindawi.com/journals/np/2016/1320423.pdf · treatments) may be a promising approach to treat ADHD. e analysis indicated

Review ArticleNatural Product-Derived Treatments forAttention-DeficitHyperactivity Disorder Safety Efficacy andTherapeutic Potential of Combination Therapy

James Ahn1 Hyung Seok Ahn2 Jae Hoon Cheong3 and Ike dela Pentildea1

1Department of Pharmaceutical and Administrative Sciences Loma Linda University Loma Linda CA 92350 USA2School of Medicine Chungnam National University Daejeon 301-747 Republic of Korea3Department of Pharmacy Sahmyook University Seoul 139-742 Republic of Korea

Correspondence should be addressed to Ike dela Pena idelapenalluedu

Received 9 November 2015 Revised 30 December 2015 Accepted 10 January 2016

Academic Editor Daniel Fung

Copyright copy 2016 James Ahn et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Typical treatment plans for attention-deficithyperactivity disorder (ADHD) utilize nonpharmacological (behavioralpsychosocial)andor pharmacological interventions Limited accessibility to behavioral therapies and concerns over adverse effects ofpharmacological treatments prompted research for alternative ADHD therapies such as natural product-derived treatments andnutritional supplements In this study we reviewed the herbal preparations and nutritional supplements evaluated in clinicalstudies as potential ADHD treatments and discussed their performance with regard to safety and efficacy in clinical trials We alsodiscussed some evidence suggesting that adjunct treatment of these agents (with another botanical agent or pharmacological ADHDtreatments) may be a promising approach to treat ADHD The analysis indicated mixed findings with regard to efficacy of naturalproduct-derived ADHD interventions Nevertheless these treatments were considered as a ldquosaferrdquo approach than conventionalADHD medications More comprehensive and appropriately controlled clinical studies are required to fully ascertain efficacy andsafety of natural product-derived ADHD treatments Studies that replicate encouraging findings on the efficacy of combiningbotanical agents and nutritional supplements with other natural product-derived therapies andwidely usedADHDmedications arealso warranted In conclusion the risk-benefit balance of natural product-derived ADHD treatments should be carefullymonitoredwhen used as standalone treatment or when combined with other conventional ADHD treatments

1 Introduction

Attention-deficithyperactivity disorder (ADHD) a neu-rodevelopmental disorder characterized by the core symp-toms of hyperactivity inattentiveness and impulsivity [1] iscurrently regarded as the most common neuropsychiatricdisorder among children [2] Furthermore while this disor-der is most often diagnosed during childhood it may alsoaffect an individual throughout life [3] It is crucial to developefficacious treatments for ADHD given its serious academicsocial and familial consequences along with the risk ofincurring comorbid conditions and later substance abuse [4]

A number of treatment strategies have been suggestedfor ADHD since its recognition as a specific disorder in the1970s Presently typical treatment plans utilize a nonphar-macological (behavioralpsychosocial) and pharmacological

interventions or a combination of both [5] A prominent non-pharmacological intervention in ADHD is behavioral ther-apy (behavior modification) which showed promise espe-cially in youth and young adult ADHD patients In principlebehavioral therapy operates via rewarding desired behaviorswith positive reinforcement and discouraging problematicbehaviors by introducing limits and consequences [6 7]Another type of behavior modification focuses on socialskills training which is conducted in a group setting whereparticipants are taught by a therapist or qualified teacherappropriateacceptable social behaviors which they (patients)are then encouraged to practice and repeat [7 8] Otherapproaches to ADHD therapy include memory trainingthat employs computer software (Cogmed) neurofeedbackelectroencephalography biofeedback green space medita-tion yoga exercise and acupuncture in order to achieve

Hindawi Publishing CorporationNeural PlasticityVolume 2016 Article ID 1320423 18 pageshttpdxdoiorg10115520161320423

2 Neural Plasticity

symptom management (for reviews see [9ndash11]) However asthese therapies are not widely available only a few patientscan benefit from these treatment approaches Although theyare easy to implement the need for time and professionaltherapists and also the involvement of not only the patient butalso members of the family and teachers during the courseof behavioral therapy limit the use of behavioral ADHDtherapies

ADHD has been associated with abnormalities in cat-echolaminergic function in the brain [12] The use ofmedications that increase levels of catecholamine in thebrain received widespread support as these drugs havebeen demonstrated to alleviate ADHD symptoms [12]Drugs indicated in the management of ADHD are classifiedas stimulant and nonstimulant medications [13 14] Thepredominantly used or prescribed pharmacological inter-ventions for ADHD are stimulant medications [13 14]Methylphenidate and dextroamphetamine are examples ofthese drugs which are structurally similar to endogenouscatecholamines and whose activity increases extracellulardopamine and norepinephrine levels thereby correctingthe underlying abnormalities in catecholaminergic functionsand restoring neurotransmitter imbalance [12]Nonstimulantalternatives include atomoxetine and norepinephrine spe-cific reuptake inhibitors and the antidepressants bupropionimipramine and phenelzine [15 16] Nonstimulant alterna-tives have also been reported to increase catecholamine levelsin the brain resulting in behavioral improvement Howevernonstimulant medications have been found to be inferior tostimulant treatments on efficacy endpoints [13 16 17]

While pharmacological treatments generally improveADHD symptoms for most children 20ndash30 of affectedindividuals are nonresponders or are unable to tolerateadverse side effects of these drugs [11 18] Some of the sideeffects of stimulant medications include headache insomniaand decreased appetite motor tics nausea and abdominalpain [5 15 18] Concerns over long-term exposure risks alsodiscourage parents to medicate their children with stimulantdrugs [17] Furthermore the high likelihood for dependencediversion and abuse particular to drugs classified as scheduleII (ie stimulants) limits the use of stimulant medicationsas ADHD has been also associated with increased risk ofsubstance use disorder [17]

Due to concerns over the safety and efficacy of cur-rent pharmacological ADHD interventions there has beengrowing interest in the development of alternative treatmentssuch as natural product-derived ADHD treatments includingbotanical or herbalmedicines vitamins minerals and aminoacids [9ndash11] These alternative treatments are appealing toparents who desire for more ldquonaturalrdquo interventions for theirchildren [9 10] Approximately 50 of parents of ADHDchildren used these treatments alone or in combination withother drugs or substances [19ndash22] In this study we providea descriptive review of natural product-derived ADHD treat-ments including complementary ADHD interventions suchas vitamins minerals and other nutritional supplementsreport findings of clinical trials which evaluated efficacyand safety of these interventions and discuss the poten-tial mechanism(s) by which these agents improve ADHD

symptoms The botanical agents are enumerated in Table 1and Table 2 summarizes the vitamins minerals and othernutritional supplements evaluated for ADHD treatmentFurthermore we also discuss the findings of studies whichevaluated safety and efficacy of combining botanical agentsor pharmacological ADHD treatments to treat ADHDTheseinformation are summarized in Table 3

2 Methods

Searches were made in the electronic databases PubMedPyschINFO andThe Cochrane Library for English languagearticles from 2001 up to December 1 2015 PubMed wasused to search ADHD search terms in combination withparticular natural product-derived treatments The searchstrategy employed included combining these keywords ldquonat-ural productsrdquo ldquoplantrdquo ldquovitaminsrdquo ldquomineralsrdquo ldquoessentialfatty acidsrdquo ldquoamino acidsrdquo ldquocombination natural prod-uctsrdquo or ldquocombination with methylphenidaterdquo and ldquoADHDrdquoor ldquoattention-deficithyperactivity disorderrdquo This processyielded 671 papers covering a wide range of research articletypes As we were interested only in natural product-derivedADHD treatments which were evaluated in clinical trials weconcentrated on open-label randomized controlled trials aswell as observational studies Moreover the inclusion crite-ria included samples consisting of children and adolescentADHD patients (below 18 years of age) as well as samplesize ge 10 The number of English language articles that werereviewed for this paper was 30

3 Results

31 Pycnogenolreg (French Maritime Pine Bark Extract) Pyc-nogenol is a standardized extract derived from the bark ofthe French maritime pine (Pinus pinaster) This extract isrich in catechin phenolic acids procyanidins and taxifolineach with multiple biologic effects [30 31] Several studieson Pycnogenol showed its potentiality in improving ADHDsymptoms in patients Most notably a double-blind placebo-controlled trial with 61 participants (ages 6ndash14 years) reportedthat Pycnogenol treatment (1mgkgday) for 1 month alle-viated ADHD symptoms particularly episodic hyperactivityand inattentiveness and improved visual-motor coordina-tion [30] One month after termination of Pycnogenol therewas a relapse of symptoms in ADHD participants The latterstudy also assumed that Pycnogenolrsquos therapeutic benefitswere mediated via an increase in nitric oxide productionwhich modulates dopamine and norepinephrine release andintake [30] Pycnogenol reportedly producedmild side effectssuch as gastric discomfort Nevertheless the relatively smallnumber of participants treatedwith Pycnogenol and the shortduration of the study limit the generalization of the studyrsquosfindings It is noteworthy however that significant effectsof Pycnogenol were observed coupled with minimal sideeffects supporting the suggestion that it could be used as analternative ADHD treatment [30]

Another randomized placebo-controlled study inves-tigating efficacy of Pycnogenol reported improvement inattention along with reduction in oxidative DNA damage

Neural Plasticity 3

Table1Clinicaltrialsevaluatin

gsafetyandeffi

cacy

ofbo

tanicalagentsfor

ADHD

Stud

yBo

tanicalagent

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Davee

tal[23]

Bacopa

(Bacopamonnieri)

Standardized

Bacopa

monnieriextract(SBM

E)(225

mgday)for

6mon

ths

Open-labelstudy

31child

ren

6ndash12years

oldwith

ADHD

Redu

ctionof

ADHD

symptom

s(restlessness

poor

self-control

inattention

impu

lsivity

etc)

Neuroprotectio

nregu

lationof

dopamine

andinhibitio

nof

cholinesterase

Safeandwelltolerated

Mild

gastrointestinal

sidee

ffects

Uebel-

von

Sand

ersle

benetal

[24]

Ginkgo

biloba

Ginkgo(EGb761reg)

240m

gdailygiven

for3

to5weeks

Openclinicalpilo

tstudy

20child

renwith

ADHD

Improvem

ento

fADHD

core

symptom

sIm

provem

entin

cerebrovascularb

lood

flow

reversalof

5-HT1

andno

radrenergic

receptor

redu

ctions

Reverseinh

ibition

ofMAO

-AandMAO

-B

Very

lowrateso

fmild

adversee

ventsd

uring

observationalp

eriod

Salehi

etal[25]

Ginkgo

biloba

Ginkgo

biloba

(80ndash

120m

gday)

ormethylphenidate

(20ndash

30mgday)for

6weeks

Rand

omized

doub

le-blin

dcontrolled

trial

50child

ren

6ndash14years

oldwith

ADHD

(119899=25Ginkgo

biloba

versus119899=25

methylphenidate)

Improvem

ento

fADHD

symptom

sLesseffectiv

ethan

methylphenidate

Lesser

sidee

ffects

(headacheinsomnia

andlossof

appetite)than

methylphenidate

Leee

tal[26]

Ginseng

Korean

redginseng

(1000

mgb

id)a

ndplacebotwicea

dayfor8

weeks

Observatio

nalstudy

18child

ren

6ndash14years

oldwith

ADHD

Improvem

entin

attention

Noo

tropice

ffecton

CNS

Increaseddo

paminea

ndno

repineph

rinelevels

Neuroprotectiv

eeffects

Taste

aversio

nand

repu

lsion

toginseng

Koetal[27]

Ginseng

Korean

redginseng

extract(1g

KRG

extractp

ouch)twicea

day

for8

weeks

Rand

omized

doub

le-blin

dplacebo-

controlledtrial

70child

ren

6ndash15years

oldwith

ADHD(119899=33

KRGversus119899=37

placebo)

Improvem

ento

fhyperactivity

and

inattentionsymptom

sDecreased

quantitative

electro

enceph

alograph

ythetabetaratio

Norepo

rted

adverse

events

sidee

ffects

Lietal[28]

Ningdong

Ningdon

g(5mgkgday)

versus

methylphenidate

(1mgkgday)for8

weeks

Rand

omized

doub

le-blin

dmethylphenidate-

controlled

trial

72child

ren

6ndash13years

oldwith

ADHD(119899=36

Ningdon

gversus119899=36

methylphenidate)

Similare

fficacy

tocontrol

(methylphenidate)

Regu

lationof

dopamine

byincreasin

gHVA

concentrationin

thes

era

Hypersomnia

Akh

ondzadeh

etal

[29]

Passion

flowe

rPa

ssiflora

incarnata

Dou

ble-blind

rand

omized

methylphenidate-

controlledclinical

trial

34child

renwith

ADHD

Improvem

ento

fADHD

symptom

sNot

specified

Decreased

appetitea

ndanxietynervou

sness

comparedwith

methylphenidategrou

p

4 Neural Plasticity

Table1Con

tinued

Stud

yBo

tanicalagent

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Trebaticka

etal

[30]

Pycnogenol

Pycnogenol(1mgkgday)

orplacebotre

atmentfor

4weeks

Rand

omized

doub

le-blin

dplacebo-controlledstu

dy

61child

ren

6ndash14

years

oldwith

ADHD(119899=44

Pycnogenolversus

119899=17placebo)

Attenu

ationof

hyperactivity

and

improvem

ento

fattention

visual-m

otoric

coordinatio

nand

concentration

Influ

ence

oncatecholam

ineformation

ormetabolism

Increasedprod

uctio

nof

nitricoxidew

hich

mod

ulates

dopamine

andno

repineph

rine

releasea

ndintake

Mild

sidee

ffects

inclu

ding

slownessand

gastric

discom

fort

Chovanovae

tal

[31]

Pycnogenol


orplacebotre

atmentfor

4weeks

Rand

omized

doub

le-blin


dy

61ou

tpatient

child

ren

6ndash14yearso

ldwith

ADHD(119899

=un

specified

Pycnogenolversus

placebo)

Improved

attention

redu

ctionin

oxidative

damage

Antioxidant

prop

ertie

sNorepo

rted

adverse

events

sidee

ffects

Weber

etal[32]

StJohnrsquos

wort

Rand

omized

doub

le-blin


dy

56child

ren

6ndash17years

oldwith

ADHD(119899=27

SJW

versus119899=27

placebo)

Nosig

nificant

improvem

entinADHD

symptom

s

Norepo

rted

adverse

events

sidee

ffects

Razlo

getal[33]

Valer

ian(Valeriana

officin

alis)

Dou

ble-blindplacebo-

controlledclinicaltria

l

30child

ren

5ndash11years

oldwith

ADHD

(119899=10Va

leriana

officin

alismother

tincture(VO

MT)

or119899=103x

potencyof

VOMTversus119899=10

placebofor3

weeks)

Improvem

ento

fADHD

symptom

sinVO

MTor

3xpo

tencygrou

pin

comparis

onto

placebo

inparticularinatte

ntion

impu

lsivityand

or

hyperactivity

Inhibitio

nof

the

breakd

ownof

GABA

inthec

entralnervou

ssyste

m

Norepo

rted

adverse

events

sidee

ffects

Neural Plasticity 5


gsafetyandeffi

cacy

ofnu

trition

alsupp

lementsforA

DHD

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Torriolietal[34]

Acetyl-L-carnitin

e(LA

C)LA

C(500

mg2tim

esday)

orplacebofor12mon

ths

Rand

omized

doub

le-blin

dplacebo-

controlledparallel

multic

enterstudy

51child

ren(A

DHDand

Fragile

Xsynd

rome)

6ndash13yearso

ld(119899=24

ALC

versus119899=27

placebo)

Redu

ctionof

ADHD

symptom

sversus

Placeboon

Clinical

GlobalImpressio

nsParentalRa

ting

Mod

ulationof

neural

transm

issionby

increasin

gacetylcholine

synthesis

stim

ulatingits

releasea

ndreleaseo

fdo

pamineinthe

stria

tum

invario

usbrain

region

s

Noadversee

ventssid

eeffectsrepo

rted

Arnoldetal[35]

Acetyl-L-carnitin

e(AL

C)ALC

inweight-b

ased

doses

from

500to

1500

mgb

idor

placebofor16weeks

Multisite

parallel-g

roup

doub

le-blin

drand

omized

pilottria

l

112child

ren

5ndash12years

old(119899=53

Acetyl-L-carnitin

eversus119899=59placebo)

Acetyl-L-carnitin

esuperio

rtoplaceboin

inattentives

ubtype

Noadversee

ventssid

eeffectsrepo

rted

Richardson

and

Puri[36]

Essentialfattyacids

Highlyun

saturatedfatty

acid

(HUFA

)EP

A186m

gday

DHA480m

gday

120574-lino

lenica

cid96

mg

vitamin

E60

IUcis-lin

oleic

acid

864m

gAA42

mgand

thym

eoil8m

gor

oliveo

il(placebo

)for12weeks

Rand

omized

doub

le-blin

dplacebo-

controlledstu

dy

41child

ren

9participantswith

drew

before

thee

ndof

12-w

eekperio

d8ndash12yearso

ld(119899=15

HUFA

versus119899=14

placebo)

Attenu

ationof

ADHD

symptom

sfore

xample

inattention

hyperactivity

improvem

entin

cogn

ition

andem

otion

Influ

ence

onsig

nal

transductio

nrelevant

toneuron

alstructure

developm

entand

functio

ns

Upsetsto

machand

difficulty

swallowing

Stevense

tal[37]

Essentialfattyacids

PUFA

supp

lement

comprise

dof

480m

gDHA

80mgEP

A40m

garachido

nica

cid(A

A)

96mgGLA

and

24mg

alph

a-tocoph

erylacetateo

ran

oliveo

ilplacebofor4

mon

ths

Rand

omized

doub

le-blin

dplacebo-

controlledstu

dy

50child

ren(girlsa

ndbo

ys)119899=25PU

FAsupp

lementatio

n119899=25

placebo

Clearb

enefitfor

all

behaviorsc

haracteristic

ofADHDwas

not

observed

Treatm

enteffectsfor

cond

uctand

attentionas

wellasw

ithclinical

improvem

entsin

oppo

sitionald

efiant

behavior

Mediatio

nof

abno

rmal

neuron

alsig

nalin

gthat

results

inaberrant

behaviors

Not

specified

6 Neural PlasticityTa

ble2Con

tinued

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Sinn

andBryan

[38]

Essentialfattyacids

LC-PUFA

capsules

containing

400m

gfishoil

and100m

gevening

prim

rose

oilw

ithEP

A(93m

g)D

HA(29m

g)G

LA(10m

g)and

vitamin

E(18mg)

orplaceboSix

activ

eor6

placebocapsules

perd

ayfor15weeks

Rand

omized

doub

le-blin

dcrossover

placebo-controlledstu

dy

132child

ren(data

availablefor

104and87

child

ren)

7ndash12yearso

ld(119899=36PU

FAsv

ersus

119899=41PU

FA+

micronu

trientsv

ersus

119899=27placebo)

Sign

ificant

treatment

effectsbasedon

parental

ratin

gof

core

ADHD

symptom

sinbo

thPU

FAgrou

psversus

placebo

Mod

ulationof

neural

cellsig

nalin

gand

neurotransmitter

processes

PUFA

swith

other

nutrientssuchas

vitC

B 3and

B 6mod

ulates

PUFArsquosrolein

the

synthesis

ofprostaglandins

and

chem

icalsimpo

rtantfor

biologicalandbrain

functio

n

Noadversee

ventssid

eeffects

Sinn

etal[39]

Essentialfattyacids

LC-PUFA

capsules

containing

400m

gfishoil

and100m

gevening

prim

rose

oilw

ithEP

A(93m

g)D

HA(29m

g)G

LA(10m

g)and

vitamin

E(18mg)

orplaceboSix

activ

eor6

placebocapsules

perd

ayfor15weeks

Rand

omizedone-w

aycrossoverplacebo-

controlledstu

dyPh

ases

1and

2

Phase1119899=129child

ren

with

ADHD(PUFA

versus

PUFA

+multiv

itaminsminerals

versus

placebofor15

weeks)

Phase2

119899=104

child

renwith

ADHD

(PUFA

PUFA

+multiv

itaminm

inerals

andplacebofor15

weeks)

Improved

abilityon

attentioncontroland

vocabu

lary

perfo

rmance

durin

gph

ase2

Influ

ence

onmetabolic

andneuralactiv

ities

Increasin

gdo

pamine

activ

ityin

thefrontal

lobe

Twocaseso

fnauseaa

ndon

eepisode

ofno

sebleed

Manor

etal[40

]

Essentialfattyacids

2capsules

twicea

dayof

phosph

atidylserin

e(PS

)containing

omega-3(300

mg

ofPS

and120m

gof

EPA+

DHA)o

rcellulose

capsules

asplacebofor15weeks

Rand

omized

doub

le-blin

dsin

gle-centerplacebo

-controlledtrial

200child

ren(6ndash13y

ears

old)

rand

omlyassig

ned

toPS

-omega-3capsules

orplacebo

119873=162child

ren

completed

15weeks

oftre

atment(119899=110PS

-om

ega-3119899=52

placebo)

Improvem

ento

fADHD

symptom

s(im

pulsivity

inattention

moo

dand

behavior

issue)

Maintenance

ofintegrity

ofcellmem

branes

Influ

ence

ondo

paminergica

ndcholinergics

ystems

Increasin

gom

ega-3

LC-PUFA

which

improves

behavioral

sensoryand

neurologicaldysfu

nctio

n

Mild

adversee

vent

profi

leG

Idisc

omfort

atop

icderm

atitis

nauseaticsand

hyperactivity

Raze

tal[41]

Essentialfattyacids

EFAcapsules

containing

240m

gof

linoleica

cid(LA)

60mgof

alph

a-lin

olenicacid

(ALA

)95

mgof

mineraloil

and5m

gof

a-tocoph

erol(as

anantio

xidant)2

timesday

orplacebovitC(500

mg

ascorbicacid)2

timesday

for7

weeks

Rand

omized

doub

le-blin

dplacebo-controlledtrial

73child

ren

7ndash13years

old63

child

ren

completed

thes

tudy

(119899=39EF

Asupp

lement

versus

39placebo

vitamin

C)

Both

treatments

amelioratedsome

ADHDsymptom

sNo

differenceineffi

cacy

betweentre

atments

Improvem

entin

behavioralsensoryand

cogn

itive

functio

ns

Noadversee

ventssid

eeffectsrepo

rted

Neural Plasticity 7

Table2Con

tinued

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Voigtetal[42]

Essentialfattyacids

345m

gof

DHAperd

ay(119899=32)o

raplacebocapsule

(119899=31)for

4mon

ths

Rand

omized

doub

le-blin

dplacebo

controlledstu

dy

54child

ren6ndash

12years

old(119899=27

docosahexaenoica

cid

(DHA)v

ersus119899=27

placebo)

DHAsupp

lementatio

ndidno

tsignificantly

improveinanyob

jective

orsubjectiv

emeasure

ofADHDsymptom

s

Welltolerated

andno

adversee

ffectsw

ere

repo

rted

Hira

yamae

tal

[43]

Essentialfattyacids

DHAgrou

pferm

ented

soybeanmilk

(600

mg

DHA12

5mL3week)bread

rolls

(300

mgDHA45g

2week)

andste

amed

bread

(600

mgD

HA60g

2w

eek)

orplacebofood

scon

taining

oliveo

ilinste

adof

DHA-

rich

fishoilfor

2weeks

Rand

omized

doub

le-blin


dy

40child

renwith

ADHD

6ndash12yearso

ld(119899=20

docosahexaenoica

cid

(DHA)v

ersus119899=20

placebo)

DHAsupp

lementatio

ndidno

timprove

ADHD-related

symptom

s

Noserio

ussid

eeffects

were

repo

rted

inthe

study

Kono

faletal[44]

Iron

80mgferrou

ssulfatetablets

orplaceboon

cedaily

inthe

morning

for12weeks

Rand

omized

doub

le-blin

dplacebo-controlledpilot

trial

23ADHDchild

renwith

lowserum

ferritinlevel

(lt30

ngm

L)5ndash8y

ears

old(119899=18iro

nversus

119899=5placebo)

Improvem

ento

fhyperactiveim

pulsive

andinattentive

symptom

sintheA

DHD

ratin

gscale

Iron

isac

ofactorinthe

synthesis

ofbo

thno

repineph

rinea

nddo

pamine

Minor

sidee

ffectsw

ere

repo

rtedsuchas

nausea

constip

ation

and

abdo

minalpain

Mou

sain-Bosce

tal[45]

Vitamin

B6andmagnesiu

mADHDchild

ren

magnesiu

m-vitamin

B6(M

g-B6

)regim

en(6

mgkgd

Mg06m

gkgd

vit-B

6)for

sixmon

thsC

ontro

lsdidno

treceiveM

g-B6

Openstu

dy

76child

ren(m

eanage

69y

ears13girls

and27

boys)(40

ADHD

child

renamp36

healthy

child

ren)

Attenu

ationof

hyperactivity

and

aggressiv

enessS

choo

lattentionwas

also

improved

Vitamin

B6facilitates

thep

rodu

ctionof

the

serotonin

Magnesiu

misa

nonspecific

inhibitoro

fcalcium

andNMDA

channels

Magnesiu

mcan

influ

ence

catecholam

ine

signalin

g

Norepo

rted

sidee

ffects

Bilicietal[46]

Zinc

150m

gzinc

sulfateor

150m

gsucrose(placebo)

daily

for12

weeks

Rand

omized

doub

le-blin

dparallel-g

roup

placebo-controlledtrial

400child

ren6ndash

14years

old(119899=202zinc

versus

119899=198placebo)

Zinc

sulfatebette

rthan

placeboin

decreasin

ghyperactivity

and

impu

lsivityand

improvingsocialization

butn

otinattention

Increasedzinc

levels

necessaryforc

ognitiv

edevelopm

ent

Noserio

ussid

eeffects

repo

rtedM

etallic

taste

was

acom

mon

complaint

8 Neural Plasticity

Table2Con

tinued

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Akh

ondzadeh

etal

[47]

Zinc

Zinc

sulfate(55m

gday)

+methylphenidate

(1mgkgday)o

rsucrose

(placebo

)55m

g+

methylphenidate

(1mgkgday)for

6weeks

Rand

omized

doub

le-blin

dclinical

trial

44child

ren

5ndash11years

old(119899=22

methylphenidate+zinc

versus119899=22

methylphenidate+

placebo)

Sign

ificantlygreater

treatmenteffects(as

per

parent

andteacher

ratin

gscales

cores)in

zinc

sulfatewith

methylphenidate

treatmento

verp

lacebo

with

methylphenidate

Zinc

regulates

dopamine

functio

nindirectly

throug

hits

actio

non

melaton

in

Nauseaa

ndmetallic

taste

werec

ommon

complaintsOverallit

was

welltolerated

Arnoldetal[48]

Zinc

Zinc

115mgday(oncea

day)

orZinc

230

mgday

(twicea

day)

orplacebo(8

weeks)am

phetam

ine

5ndash15mgdaily

(based

onthe

weight)

Durationof

experim

entw

as13

weeks

(8weeks

controlled

+5weeks

amph

etam

ine

add-on

)

Rand

omized

doub

le-blin


trial

52child

ren6ndash

14years

old(119899=20Zinc

1or

119899=8Zinc

2versus

119899=24placebo)

Noappreciable

differenceb

etweenbo

thdo

sageso

fzinca

ndplacebo

Gastro

intestinal

discom

fortrepo

rted

by1

patie

nt

Neural Plasticity 9

Table3Clinicaltrialsdemon

stratingeffi

cacy

ofcombinatio

ntherapyof

botanicalagentsa

ndherbssupp

lementswith

methylphenidatein

treatingADHD

Stud

yMetho

dsParticipants

Outcomes

Com

ments

Lyon

etal[49]

Ginkgo

biloba

andGinseng

Ginkgo

biloba

extract

(50m

g)plus

American

ginsengPa

nax

quinquefo

lium

(200

mg)

twiceday

(com

binatio

nprod

uct)

Open

pilotstudy

36child

ren

3ndash17years

oldwith

ADHD

Improvem

ento

fADHD

symptom

s(hyperactiv

ity

impu

lsivenessand

anxiety)

Five

participants

repo

rted

adversee

vents

(increasedADHD

symptom

saggressiv

enesssw

eatin

gheadacheand

tiredness)on

ly2

considered

related

tothe

study

Wangetal[50]

Jingling

oralan

dmethylphenidate

Methylphenidate

(10ndash

40mgd)

Rand

omizedblin

ded

study

119899=50ADHDchild

ren

with

transie

nttic

disorder

Sign

ificant

improvem

ent

ofADHDsymptom

sas

wellastics

Com

binatio

ntherapy

moree

ffectivethan

methylphenidatealon

ein

improvingADHD

andtic

symptom

s

Dingetal[51]

Yizhiand

methylphenidate

Rand

omized

methylphenidate-

controlled

trial

210child

renwith

hyperkineticsynd

rome

Sign

ificant

improvem

ent

inADHDsymptom

sin

thosetaking

combinatio

ntherapy

comparedto

either

given

asmon

otherapy

Yizhih

adfewer

side

effectswhengivenalon

eor

incombinatio

nthan

methylphenidate

Akh

ondzadeh

etal

[47]

Zinc

sulfateand

methylphenidate

Rand

omized

doub

le-blindand

methylphenidate+

placebocontrolledtrial

44child

ren(26bo

ys18

girls)5ndash11yearso

ldwith

ADHD

Improved

parent

and

teacherratingscale

scores

fortho

sesupp

lementedwith

zinc

sulfateas

anadjunct

Side

effectsrepo

rted

anxietylossof

appetite

nauseaheadache

abdo

minalpain

insomniaandmetallic

taste

10 Neural Plasticity

and normalization of homeostatic antioxidant status inADHD patients treated for 1 month with the compound [31]A month after Pycnogenol treatment the total antioxidantstatus (TAS) was increased in ADHD children (ADHDchildren showed lower TAS levels at the beginning of thestudy compared with healthy controls) and was significantlyelevated after 1 month of termination of Pycnogenol treat-ment Oxidative stress is believed to be a contributing factorto the etiology of ADHD [52] The improvement of ADHDsymptoms in ADHD patients given Pycnogenol has beenattributed to the drugrsquos potent antioxidant effects [52] Someancillary benefits of Pycnogenol were normalization of theconcentration of urinary catecholamines in children withADHD and improvement in cerebral blood flow to regionsof the brain implicated in this disorder [11 53] Of note nei-ther Pycnogenol nor the positive control methylphenidateoutperformed placebo on any ADHD rating scale [54] Insummary Pycnogenol is a promising botanical alternative inthemanagement of ADHD symptoms althoughmore studiesare required before it can be used as an ADHD treatment

32 St Johnrsquos Wort This herb ldquoHypericum perforatumrdquowhile best known for its antidepressant qualities was foundto have beneficial effects on other psychiatric disordersincluding obsessive compulsive disorder major and bipolardepression somatization disorder and social phobia [55] Ithas been suggested that the mechanism by which St Johnrsquoswort produces its therapeutic effects involves inhibition ofthe reuptake of dopamine serotonin and norepinephrine Apreliminary study reported improvement in ADHD symp-toms of 3 ADHD patients (ages 14ndash16) given St Johnrsquos wort[56] However a more stringent randomized double-blindplacebo-controlled trial found that 8 weeks of St Johnrsquos worttreatment (300mgday) did not alleviateADHDsymptoms in54 ADHDpatients (aged 6ndash17) [32] In light of these findingsmore studies are required to determine efficacy of St Johnrsquoswort in the treatment of ADHD While the above studies didnot report adverse effects of St Johnrsquos wort investigations onthe safety of this treatment are still necessary

33 Ginseng Ginseng contains ginsenosides a class of phy-tochemicals with neuroprotective and antioxidant effects [2627] Ginseng has also been reported to improve ADHDsymptoms [27] In addition ginsenosides are reported toelevate levels of dopamine and norepinephrine hence theycould potentially be used to treat ADHD Ginsengrsquos thera-peutic benefits in ADHDwere confirmed in an observationalstudy involving ADHD participants (18 kids ages 6ndash14)given Korean red ginseng (KRG Panax ginseng) twice perday for 8 weeks (1000mg twice daily) In this study KRGimproved attention as measured by significant differencesin omission errors measured by the computerized ADHD-diagnostic system (ADS) (7856 plusmn 4333 at baseline 5517 plusmn2144 at 8 weeks 119901 lt 0023) [26] Omission errors inADS measure inattentiveness The significant decrease inomission errors has been associated with the restorationof impaired cognitive function in children with ADHDNevertheless the small population size limits generalizabil-ity of the studyrsquos findings A large-scale study with larger

number of participants is necessary as well as studieswhich assess long-term efficacy of KRG supplementation[27]

Another study (randomized double-blind and placebo-controlled) reported similar results in that participants(ADHD patients aged 6ndash15 119899 = 33) given one pouch of KRG(1 g KRG extractpouch) twice per day showed improvementin their inattention and hyperactivity scores after an 8-weektreatment course compared with the control group (119899 =37) [27] Accordingly the KRG group displayed significantlydecreased inattentionhyperactivity scores compared withthe control group at week 8 (least squaredmeans of the differ-ences in inattention adjusted for baseline scores are as followsminus225 versus minus124 119901 = 0048 hyperactivity minus153 versusminus061 119901 = 0047) They also showed decreased quantitativeelectroencephalography thetabeta ratio in comparison withthe control group (least squared means of the differences areas follows minus094 versus minus014 119901 = 0001) The side effectprofiles of ginseng included headache fatigue perspirationand subjective issues with the taste of the ginseng product[26] Ginsengrsquos potential use as both alternative and adjunctADHD treatment appears promising given the minimalsafety concerns and remarkable efficacy

34 Ginkgo biloba A unique species of tree native to EastAsia Ginkgo biloba has been extensively studied for itsmemory-enhancing effects [25] Currently G biloba is usedas an alternate treatment in patients with dementia or mem-ory impairment [25 49] Studies also indicate that G bilobamay have therapeutic benefits in ADHD For instance Uebel-von Sandersleben et al [24] reported improvement in overallquality of life ADHD core symptoms and Continuous Per-formance Test (CPT) performance in children givenG biloba(240mgdaily) for 3ndash5 weeks A reduced dose of G biloba(50mg) when combined with ginseng (200mg) for 4 weeksof treatment significantly improved ADHD symptoms in atest group of 36 children (ages 3ndash17) as quantified byConnersrsquoParent Rating Scale-Revised (long version) (CPRS-R [L])[24] Accordingly there was significant improvement in eachof the 3 areas which are most troublesome in ADHD (iehyperactivity cognitive problems and oppositional behavior)in at least 50 of the subjects given G biloba (50mg) andginseng (200mg) up to 4 weeks after treatment Reportedside effects of G biloba were observed for example subjectsbecame more impulsive hyperactive aggressive emotionaland tired and manifested increased sweating [24 25] Gbilobarsquos beneficial effects have been linked to various activitiessuch as improvement in cerebrovascular blood flow (allevi-ating hyperactivity) reversal of serotonergic (5-HT) 1A andnoradrenergic receptor reductions and inhibition of bothmonoamine oxidase- (MAO-) A and MAO-B in the brain[24 25]WhileG biloba did produce improvement in ADHDsymptoms a trial by Salehi et al [25] conducted over a 6-weekperiod (double-blind randomized and placebo-controlled119899 = 50 children) found that G biloba (80ndash120mgday)was inferior to methylphenidate in efficacy endpoint Moreformal clinical trials are required with longer duration andrigorous clinical endpoints in order to prove the worth of Gbiloba in ADHD treatment

Neural Plasticity 11

35 Valerian Valerian (Valeriana officinalis) is a perinealplant with sedative and antispasmodic effect It has alsobeen traditionally used in the treatment of insomnia anxietyand restlessness [9] The efficacy of Valerian as an ADHDtreatment has been evaluated in a double-blind placebo-controlled pilot study [57] Participants (30 kids aged 5ndash11) given Valerian tincture three times a day for two weeksshowed improvement in ADHD symptoms in particularsustained inattention and impulsivity andor hyperactivity [933] Nevertheless the positive effects produced in the first twoweeks of the study were not maintained overall following oneweek of no administrationThe therapeutic effects of Valerianhave been ascribed to valerenic acid (a significant componentofValerian) acting on the receptor gamma-aminobutyric acid(GABA)A receptor [33] GABA is the brainrsquos main inhibitoryneurotransmitter and has calming effects (for review see[28]) Deficiency in GABA causes anxiety restlessness andobsessive behavior symptoms often seen in ADHD [58]Valerian is considered generally safe and its use in childrenwith ages 3ndash12 years was approved by the European ScientificCooperative on Phytotherapy However Valerian must onlybe used under medical supervision [9 10 33] More studiesare required to augment limited clinical evidence supportingefficacy of Valerian in treating ADHD

36 Ningdong Ningdong granule (NDG) is a widely usedChinese medicinal preparation for various medicinal pur-poses NDG showed promise in treating Tourettersquos syndromewhich invited studies to determine its efficacy in ADHD [28]A randomized double-blind methylphenidate-controlledtrial where 72 children with ADHD were given 5mgkgdayof NDG (119899 = 36) or 1mgkgday methylphenidate (119899 =36) for a period of 8 weeks reported that NDG was equallyeffective as methylphenidate in improving ADHD symptoms[28] Accordingly no significant difference was observedbetween the NDG and methylphenidate groups with regardto the data of teacher and parent ADHD rating scales at 8weeks after medication Furthermore NDG produced lessside effect profiles and was more tolerated by children asconfirmed by urine blood and stool analysis alongwith renaland hepatic function tests Interestingly levels of homovanil-lic acid (HVA) which is involved in dopamine regulationwere increased in the sera of NDG-treated group with noresulting change in the concentration of dopamineHence theinvestigators proposed that NDG could be a safe efficaciousalternative treatment for ADHD [28] One of the limitationsof the study however involves the lack of placebo controlin the study and the short-term outcomes More meaningfulpharmacological evidences to support the utility of NDG asan ADHD treatment are also required [28]

37 Bacopa Bacopa (Bacopa monnieri) is an Ayurvedicmedicine also known as Brahmi orwater hyssopThis naturalremedy has been used for centuries to modulate memoryconcentration and learning [9] Exploratory studies showedthat Bacopa improves memory and learning in children withADHD [9] These findings were further supported by thefindings of an open-label study which showed that Bacopaextract (225mgday for 6 months) produced significant

improvement in ADHD symptoms of participants (31 chil-dren ages 6ndash12) [23] In this study [29] the symptom scoresfor restlessness were reduced in 93 of children whileself-control was improved in 89 of ADHD participantsThe attention-deficit symptoms were also attenuated in 85of children Moreover learning problems impulsivity andpsychiatric problems symptom scores were reduced for 7867 and 52of children respectively It was further reportedthat 74 of the children exhibited up to a 20 reductionwhile 26 of children displayed between 21 and 50reduction in the total subtests scores The efficacy of Bacopain this context has been attributed to its neuroprotective andantioxidant effects as well as regulation of dopamine andinhibition of cholinesterase [9 23] Someminor gastrointesti-nal side effectswere reportedwith the use of Bacopa althoughit was well tolerated by children [23] Further studies arewarranted to confirm the safety and efficacy of this botanicalagent when used as an ADHD treatment

38 Passion Flower Passion flower is comprised of thefragmented or cut dried aerial parts of Passiflora incarnataL which is a traditional remedy for anxiety and ADHD[29 59] Effect of passion flower in alleviating ADHDsymptoms was tested in 34 children with ADHD randomizedto receive tablets of Passiflora (004mgkgday twice daily)or methylphenidate (1mgkgday twice daily) dosed on aweight-adjusted basis for 8 weeks Both parent and teacherrating scores revealed no significant difference in the clini-cal benefits of Passiflora and methylphenidate treatment inADHD children over the course of the trial (119865 = 0007 df =1 and 119901 = 093 and 119865 = 0006 df = 1 and 119901 = 094 resp)Moreover side effect profile of Passiflora was less comparedwith methylphenidate [59] As the study was conducted in asmall population of patients the results of this study need tobe validated in larger trials

39 Emerging Natural Product-Derived ADHD TreatmentsEvidence from Preclinical Studies

391 Oroxylin A Oroxylin A (57-dihydroxy-6-methoxyfla-vone) is a flavonoid isolated from the root of Scutellariabaicalensis Georgi a herb commonly found in East Asia[60] Oroxylin A is an antagonist of the GABAA receptor[60] Furthermore its biological activities including antiox-idant anti-inflammatory and antiallergy as well as memory-enhancing and neuroprotective effects provide basis forits potential therapeutic use in ADHD Preclinical studiesshowed that Oroxylin A or its derivative (57-dihydroxy-6-methoxy-41015840-phenoxyflavone) produced improvement ofADHD-like behaviors in spontaneously hypertensive ratsanimal models of ADHD [61 62] The therapeutic activitiesof Oroxylin A have been ascribed to enhanced dopamineneurotransmissionOngoing studies are investigating efficacyof Oroxylin A in ADHD patients

392 YY162 YY162 is a combination pharmaceutical prod-uct consisting of terpenoid-strengthened G biloba and gin-senoside Rg3 from ginseng A recent study showed improve-ment of ADHD-like symptoms induced by Aroclor1254


in mice given YY1612 [63] The degree of alleviation ofADHD-like symptoms induced by YY1612 was found to becomparable to that exerted by methylphenidate YY1612 alsoproduced neuroprotective effects with minimal behavioralside effects The mediation of the ADHD-like symptomsin mice by YY1612 is believed to be due to its antioxidantproperties and its ability to regulate and control dopamineand norepinephrine transporters [63] Further studies arerequired to show the potentiality of YY1612 as an ADHDmedication

393 Sideritis scardica The genus Sideritis plant speciesldquoSideritis scardicardquo has been used traditionally in theMediterranean region as teas and flavoring agents andalso for treatment purposes [57] Studies have shown thatS scardica extracts may have an inhibitory effect on thereuptake of three key monoamines dopamine serotoninand noradrenaline [57] Moreover an electroencephalo-gram (EEG) study showed that Sideritis treatment in ratsinduced frequency patterns comparable to those producedby methylphenidate [64] Overall these studies suggest thebenefit of Sideritis in the treatment of mental disordersincluding ADHD Further in vivo studies measuring itsefficacy in ADHD are warranted

394 Rhodiola Rhodiola (Rhodiola rosea) has been shownto stimulate CNS activity and exert adaptogenic and neu-roprotective effects [65] The antifatigue and antianxietyeffects of Rhodiola extract have been demonstrated in variousclinical trials [66 67] In view of these results Rhodiola mayhave therapeutic potential for treating anxiety disorders anddepression [68 69] No adverse side effects were reported inthe above-mentioned clinical trials making it a potentiallysafe medication Preclinical studies reported that Rhodiolamay enhance levels of serotonin by increasing the transportof serotonin precursors (eg tryptophan and 5-HTP) [70]Rhodiola also appears to inhibit the activity of acetyl-cholinesterase an enzyme which degrades acetylcholine [71]These properties of Rhodiola demonstrate its potential asan ADHD treatment No trials have been conducted to testefficacy of Rhodiola in ADHD

310 Nutritional Medicines and Supplements Previous stud-ies showed that certain vitamins minerals and amino acidsmay contribute to the pathology of ADHD (discussed below)Thus a wide range of nutritional supplements (vitaminsand minerals) have been proposed as potential adjunct andalternativeADHD treatments Because these agents are closerto food substances than drugs they do not have similarrigorous restrictions by the Federal DrugAdministration thatdrugs do have and can be purchased over the counter [45]

3101 Vitamins Vitamins have been used as potentialadjuncts or alternative treatments for ADHD based onanecdotal evidence that they produced improvement inattentiveness and concentration in normal children [10] Asan example combining magnesium (6mgkgday) with vita-min B6 (06mgkgday) during an 8-week treatment courseimproved ADHD symptoms in children [45] with symptoms

recurring again once supplementation was discontinuedThebeneficial attributes of vitamin B6 on ADHD are attributedto its ability to influence the production of serotonin[9 58]

The effects of vitamin C treatment with alpha linolenicacid- (ALA-) rich nutritional supplementation in the formof flax oil on blood fatty acids composition and behaviorin children with ADHD were also examined [72] Thisstudy found that red blood cell membrane fatty acids weresignificantly improved in ADHDpatients receiving the abovesupplementation and alleviated ADHD symptoms in ADHDpatients as evidenced by reduction of hyperactivity scores[72] As mentioned above oxidative stress has been postu-lated to play a role in ADHD [52 73] Thus the antioxidanteffect of vitamin C may have contributed to the beneficialeffect of this supplementation regimen in ADHD childrenalong with effects of ALA (ALA is a precursor fatty acidand with elongation and unsaturation gets converted todocosahexaenoic acid which is critical for normal braindevelopment) [73 74]

Currently there is another ongoing clinical study evalu-ating the effect of tocotrienols for children with ADHD ofwhich findings are not yet reported Tocotrienols for School-going Children With ADHD (TOCAT) Tocotrienol is aform of vitamin E which is described to exert antioxidativeproperties [74] Moreover aside from antioxidant propertiestocotrienol may also inhibit phospholipase A2 enzyme whichis involved in metabolism of polyunsaturated fatty acidswhich is purportedly dysfunctional in ADHD [74 75]

While vitamins may not directly affect symptoms ofADHD they have the added benefit of replenishing anydeficiencies due to poor dietary habits [10] Neverthelesswhen initiating megadoses (ie 100 times the recommendeddaily intake) of vitamins [76] caution must be used inyounger patients as evidence supporting efficacy of vitaminsremains to be established Moreover megadoses of vitaminswere sometimes detrimental at such high doses [10 76 77]Further studies (randomized double-blind and placebo-controlled) are necessary to validate the use of vitamins totreat ADHD

3102 Minerals Another proposed alternative interventionfor ADHD is mineral supplementation Mineral deficiencieshave also been implicated in the etiology of this disordermaking supplementation a potential means of improvingADHD symptoms Minerals as cofactors have a role in thesynthesis uptake and breakdown of crucial neurotransmit-ters associated with ADHD [11 76 78] Moreover mineralssuch as magnesium and calcium are necessary for aerobicmetabolism and serve as cofactors in the degradation ofblood glucose through glycogenesis the citric acid cycleand respiratory chain in the mitochondria Enhanced energymetabolism of neurons and glial cells regulated by the mito-chondria is largely dependent on the presence of minerals aswell as vitamins (for review see [76])

A 12-week double-blind study found that children sup-plemented with zinc sulfate (150mg) showed reduced impul-siveness hyperactivity and socialization difficulties [46] Astudy by Akhondzadeh et al [47] also reported alleviation


of ADHD symptoms in children given zinc sulfate alongwith methylphenidate therapy The side effect profile provedminimal with gastrointestinal discomfort and metallic tastebeing the most common When zinc levels are low corre-sponding impairments in cognitive functions may ensue [1147]Thus it is believed that zinc supplementation would havebeneficial effects on cognitive functions However anotherstudy showed that zinc supplementation produced negligiblebeneficial effects on relieving ADHD symptoms [48] Theseopposing clinical outcomes can be attributed to geneticfactors dosage differences and nutritional status of patients[11]

Iron is another well-studied mineral that has undergoneclinical trial for the treatment of ADHD Iron is a cofactorin the synthesis of both norepinephrine and dopamine [1118] As shown in previous studies anemic children (irondeficient) exhibited attentional deficits [78] A randomizeddouble-blind placebo-controlled trial found that iron supple-mentation in children with ADHD (23 kids ages 5ndash8) provedbeneficial in relieving ADHD symptoms [44] Notably sup-plementation in childrenwithout iron-deficiency anemia hadinconsistent variable results [11 78]

Another mineral shown to improve ADHD symptomsis magnesium The involvement of this mineral in neuro-transmitter synthesis supports its potentiality as an ADHDtreatment [79] In a previous study children supplementedwith magnesium and vitamin B6 showed improvement intheir ADHD symptoms [45]

In general these findings indicate the worth of mineralsupplementation in ADHD Nevertheless a strategy sug-gested to advance the use of minerals (as well as vitamins) inADHD treatment is to combine these nutrients to adequatelyaffect the complicated biochemical pathways that may bedefective in ADHD patients [76] and to mimic the vast arrayof nutrients required for optimal brain functioning [76] Inan open-label on-off-on-off (reversal design) study involving14 ADHD children (8ndash12 years old) treated with a 36-ingredient micronutrient (vitamins and minerals) titrated upto maximum dose (15 capsulesday) for 8 weeks withdrawnfor 4 weeks and reinstated for a further 8 weeks and with-drawn again for 4 weeks improvement in ADHD symptomsand mood as well as enhanced overall functioning duringtreatment phases with deterioration in ADHD symptomsmood and overall functioning during the withdrawal phaseswas observed in ADHD participants [80] Further statisticalanalyses also confirmed clinically and statistically significantchange between the intervention and withdrawal phaseswith large effect sizes observed before to after exposure ofmicronutrients (119889 = 12ndash22) on ADHD symptoms duringintervention phases [80] This study also found that 71 ofparticipants showed at least a 30 decrease in ADHD symp-toms by the end of the second treatment phase and 79wereidentified as ldquomuch improvedrdquo or ldquovery much improvedrdquoat the end of the second phase (5 months) based on theclinician-ratedClinical Global Impressions (CGI) Scale whenevaluating functioning generally The Strengths and Diffi-culties Questionnaire (SDQ)mdashparent versionmdashalso revealedthat these beneficial effects of micronutrients occurred acrossother areas of functioning including emotional symptoms

conduct problems and prosocial behaviors The childrenrsquosself-reports also verified the improvements There was alsoremarkable adherence to treatment and side effects weremild and transitory without safety issues after blood analysisof participants Indeed a combination of different micronu-trients may be more feasible and produce more significantclinical benefits compared with treatment with a singlemicronutrient only [76 80]

3103 Amino Acids A number of amino acids have beenshown to exert direct or indirect effects on the levels ofspecific neurotransmitters Thus they have the potential tobe used in treating ADHD Amino acids glycine L-theanineL-tyrosine taurine acetyl-L-carnitine (ALC) GABA 5-hydroxytryptophan (5-HTP) and s-adenosyl-L-methionine(SAMe) are all considered potential complementary ADHDinterventions [9 10] A significant portion of studies onamino acid supplementation has focused on ALC an aminoacid derivative One such study (randomized double-blindand placebo-controlled) utilizing ALC reported that supple-mentation with this protein derivative significantly reducedsymptoms of ADHD in particular hyperactivity and poorsocial behavior in trial participants (51 children ages 6ndash13) [34] This effect of ALC has been attributed to mod-ulation of neural transmission by increasing acetylcholinesynthesis stimulating its release and release of dopamine inthe striatum in various brain regions other than carnitinemetabolism [34] On the other hand a randomized double-blind placebo-controlled study reported conflicting findingsin that no significant effects of ALC were observed in ADHDpatients (112 children ages 5ndash12) [35]

Theanine is an amino acid found in both greenand black teas [81] This nonproteinaceous component(n-ethylglutamic acid) has garnered increasing attentionrecently due to its purported central nervous system effectsBecause of its ability to cross the blood-brain barrier theaninehas a variety of pharmacological effects most pertinent ofwhich is anxiolytic effect These effects of theanine have beenattributed to regulation of dopamine and serotonin and anincreased production of inhibitory neurotransmitters [81]Additionally it has been reported that theanine producedimprovement in selective attention during the execution ofmental tasks via modulation of alpha brain wave activityCurrently there are a handful of studies examining thetherapeutic potentials of theanine in ADHD (for review see[81]) Theanine has also been suggested for panic disorderbipolar disorder and obsessive compulsive disorder asidefrom ADHD and anxiety disorders

3104 Essential Fatty Acids Theeffects of essential fatty acids(EFAs eg omega-3 and omega-6) in treating ADHD inchildren have been recently investigated Supplementationwith these fatty acids has shownmodest success in controllingADHD symptoms [82 83] A study by Richardson andPuri [36] reported that ADHD children showed improvedattention and reduced hyperactive and defiant behaviors aftersupplementation with highly unsaturated fatty acids (com-prised of eicosapentaenoic acid (EPA) 186mgday docosa-hexaenoic acid (DHA) 480mgday 120574-linolenic acid 96mg


vitamin E 60 IU cis-linoleic acid 864mg AA 42mg andthyme oil 8mg) The influence of these fatty acids on signaltransduction relevant to neuronal structure developmentand functions may play a role in EFA-induced improvementof ADHD symptoms [36] Another study revealed improve-ment in inattention and oppositional behaviors in childrenwho received combined EFA supplementation (polyunsat-urated fatty acid (PUFA) supplement comprised of 480mgDHA 80mg EPA 40mg arachidonic acid (AA) 96mggamma-linolenic acid (GLA) and 24mg alpha-tocopherylacetate) although not all ADHD behaviors were alleviatedby this treatment regimen [37] Furthermore Sinn and Bryan[38] reported marked improvement in ADHD symptoms inchildren supplemented for 15 weeks with EFA as opposed tothose receiving placebo The same supplementation regimenalso improved attention control and vocabulary performancein ADHD children Manor et al [40] also reported improve-ment of ADHD symptoms (impulsivity inattention) andmood and behavioral problems in ADHD patients givenphosphatidylserine containing omega-3 EPA andDHA [40]The exact mechanism by which EFAs benefit ADHD isstill unresolved but may be associated with the role ofEFAs in brain development (eg effects on gene expressionneural signaling and cellular growth and functions) [10 37ndash40 82] Another proposed mechanism suggests that thesetherapeutic benefits may arise from increased dopaminergicand serotonergic activity as a result of elevated EFAs [11 4082]

In contrast other studies including randomized clini-cal trials reported no significant effectsbenefits in ADHDpatients treated with EFAs compared with the placebo group[41ndash43] A meta-analysis of randomized controlled trialswith EFAs revealed disappointing results in thatmost of thesetrials do not support robust clinical effect of EFA supplementsas a treatment for children with ADHD [84] Recent reviewsalso reported modest benefits of EFA supplementation inADHD patients [85ndash87] In summary although some studieshave reported therapeutic benefits of EFA supplementationthe current evidence for EFA as a complementary andalternative medicine for ADHD remains controversial [86]

4 Combination Treatment ApproachesEffects of Two Botanical Agents or WhenGiven with an ADHD Drug

Given the multifactorial characteristic of ADHD the man-agement of this disorder may benefit from a multimodalapproach Presently ADHDmanagement trends are favoringtreatment of ADHDwith a combination of various treatmentapproaches [88 89] Multimodal strategies are highly attrac-tive because they are more ldquoholisticrdquo and patient specificMoreover combined therapies may also help improve overallfunctioning by targeting symptoms of comorbid disorderssuch as substance use disorder compulsive disorders andlearning disabilities [58]

Most multimodal treatment approaches employ the useof stimulant medications given their wide use in managingADHD and behavioralpsychosocial therapy A multisiteclinical trial the Multimodal Treatment of ADHD (MTA)

study revealed that combination (medicinal and behavioraltreatment) and medicinal management (methylphenidate)interventions were significantly superior to behavioral orcommunity care alone for managing ADHD symptoms [88]Moreover there was a perceived advantage of combinationtreatment over single treatment (medicinal and behavioral)for managing other functioning domains such as social skillsacademics oppositional behavior and anxietydepression[89]

In contrast only a few studies have evaluated combi-nation therapy utilizing nutritionalbotanical supplementswith behavioral therapy or pharmacological ADHD agents(Table 3) What is more there are limited studies whichscreened therapeutic potential of combining a botanical agentwith another plant-derived product or nutritional supple-ments Nevertheless the findings of these studies have beenencouraging Discussed below are some of these landmarkstudies

41 Efficacy of Combinatorial Natural Product-Derived Treat-ment and Pharmacological ADHD Therapy Two Chinesemedicine herbal treatments have been previously evaluatedas adjunct treatments to methylphenidate A 2-week trial inchildren randomized to receive Yizhimixture (a combinationof 10 herbs designed to affect YinYang liver functions)methylphenidate or combination treatment reported moresignificant improvement of ADHD symptoms in childrensubjected to combination treatment than in those random-ized to either individual treatmentThere were also fewer sideeffects in children given Yizhi mixture alone or combinationtreatment than in those assigned to the methylphenidategroup [51] In another study efficacy of combination therapywith Jingling oral liquid andmethylphenidate was tested [50]This study showed that children randomized to this treatmentapproach showed greater improvement in ADHD symptomsand well as tic symptoms compared to treatment withmethylphenidate only What deserves further investigation isthe safety profile of these herbal treatments given alone or incombination with methylphenidate

In another study Akhondzadeh et al [47] performeda randomized double-blind trial to examine the poten-tial benefits of a zinc sulfate treatment alongside methyl-phenidate The result showed that methylphenidate therapywas enhanced with the addition of zinc supplementationin participants (children ages 5ndash11) Therefore combiningbotanical agents or nutritional supplements with pharmaco-logical ADHD treatment may be a promising ADHD treat-ment approach As expected with combinatorial treatmentapproaches combination therapy may enhance therapeuticefficacy or overcome therapeutic limitations of individualtreatments

42 Efficacy of Combining Two Botanical Agents The efficacyof combining American ginseng extract Panax quinque-folium (200mg) and Ginkgo biloba extracts (50mg) toalleviate ADHD symptoms was evaluated in 36 childrenaged 3ndash17 years [24] Results of this study indicated thatafter 4 weeks of treatment with this mixture 50 ofthe subjects showed improvement in each of the 3 areas


that are most troublesome in ADHD namely hyperac-tivity cognitive problems and oppositional behavior Thediverse mechanisms of these agents including their abil-ity to enhance brain functions may have been responsi-ble for the efficacy of this combined therapy [49] Nev-ertheless well-controlled trials with rigorous clinical end-points need to be undertaken before drawing definitiveconclusions on the safety and efficacy of this treatmentapproach

5 Conclusion

There are a number of available treatment options for ADHDhowever some of them may pose risks to patients [10]The botanical agents discussed in this study appear to bepromising ADHD treatments considering their therapeuticeffects and negligible negative side effects Nevertheless it hasto be noted that ADHD is a complex disorder havingmultiplecauses and thus the use of natural product-derived treat-ments alone may not sufficiently affect consistent change inADHD symptoms (see [76]) As mentioned previously morepronounced clinical benefit may be achieved by employing amultimodal treatment approach such as combination therapyof different botanical agents andormicronutrients botanicalagents and conventional pharmacological treatments andalso behavioral therapy

Although the use of natural medications for ADHD hasbeen considered as a ldquosaferrdquo approach natural products arestill far from being called as standard ADHD treatments dueto the lack of comprehensive and appropriately controlledclinical studies that interrogate both their efficacy and safetyMoreover it is challenging to compare efficacy profiles ofherb therapy with conventional pharmacological ADHDtreatments mainly because herbal preparations are notstandardized and question regarding their purity reliabilitysafety and toxicity profiles will always arise [58] Thereforeusing pure medications with known doses described mech-anisms of action and adverse effects profiles is preferablewith regard to the use of natural product-derived ADHDtreatments

The findings from recent albeit few studies whichevaluated efficacy of adjunct therapy of botanical agentsand nutritional supplements with a pharmacological ADHDtreatment or another botanical agent suggest that combina-tion therapy may be a promising approach in ADHD treat-ment Nevertheless positive findings from above-mentionedstudies need to be replicated and evidence for long-termeffectiveness and safety should be aptly demonstrated Effi-cacy of combining other botanical agents with pharma-cological agents including other medications aside frommethylphenidate (eg atomoxetine guanfacine and cloni-dine) or with behavioral therapy should also be exploredin future studies As herbs usually contain more thanone psychoactive substance and may have additive orinteractive effects with the combined treatment the risk-benefit balance of natural product-derivedADHD treatmentsshould be carefully considered when combined with othermedications

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Authorsrsquo Contribution

James Ahn and Hyung Seok Ahn contributed equally to thiswork

Acknowledgments

This research is supported in part by the School of Pharmacyof Loma Linda University (LLUSP-360034) and the KoreaHealth Technology RampD Project (Grant no A120013)

References

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[2] G Polanczyk M S de Lima B L Horta J Biederman and LA Rohde ldquoThe worldwide prevalence of ADHD a systematicreview and metaregression analysisrdquo The American Journal ofPsychiatry vol 164 no 6 pp 942ndash948 2007

[3] V A Harpin ldquoThe effect of ADHD on the life of an individualtheir family and community from preschool to adult liferdquoArchives of Disease in Childhood vol 90 supplement 1 pp i2ndashi72005

[4] S P Hinshaw L E Arnold and The MTA CooperativeGroup ldquoAttention-deficit hyperactivity disorder multimodaltreatment and longitudinal outcome evidence paradox andchallengerdquo Wiley Interdisciplinary Reviews Cognitive Sciencevol 6 no 1 pp 39ndash52 2015

[5] R T Brown R W Amler W S Freeman et al ldquoTreatmentof attention-deficithyperactivity disorder overview of the evi-dencerdquo Pediatrics vol 115 no 6 pp e749ndashe757 2005

[6] S A Safren S Sprich M J Mimiaga et al ldquoCognitivebehavioral therapy vs relaxation with educational support formedication-treated adults with ADHD and persistent symp-toms a randomized controlled trialrdquoThe Journal of the Ameri-can Medical Association vol 304 no 8 pp 875ndash880 2010

[7] ldquoADDADHD treatment in children finding treatments thatwork for kids and teensrdquo 2015 httpwwwhelpguideorgarti-clesadd-adhdattention-deficit-disorder-adhd-treatment-in-childrenhtm

[8] O J Storeboslash M Skoog D Damm P H Thomsen E Simon-sen and C Gluud ldquoSocial skills training for attention deficithyperactivity disorder (ADHD) in children aged 5 to 18 yearsrdquoTheCochrane Database of Systematic Reviews vol 12 Article IDCD008223 2011

[9] J Pellow E M Solomon and C N Barnard ldquoComplementaryand alternative medical therapies for children with attention-deficithyperactivity disorder (ADHD)rdquo Alternative MedicineReview vol 16 no 4 pp 323ndash337 2011

[10] A Bader and A Adesman ldquoComplementary and alternativetherapies for children and adolescents with ADHDrdquo CurrentOpinion in Pediatrics vol 24 no 6 pp 760ndash769 2012

[11] H R Searight K Robertson T Smith S Perkins and BK Searight ldquoComplementary and alternative therapies for


pediatric attention deficit hyperactivity disorder a descriptivereviewrdquo ISRN Psychiatry vol 2012 Article ID 804127 8 pages2012

[12] J Prince ldquoCatecholamine dysfunction in attention-deficithyperactivity disorder an updaterdquo Journal of Clinical Psy-chopharmacology vol 28 no 3 supplement 2 pp S39ndashS452008

[13] J Biederman T Spencer and T Wilens ldquoEvidence-basedpharmacotherapy for attention-deficit hyperactivity disorderrdquoThe International Journal of Neuropsychopharmacology vol 7no 1 pp 77ndash97 2004

[14] M LWolraich C JWibbelsman T E Brown et al ldquoAttention-deficithyperactivity disorder among adolescents a review ofthe diagnosis treatment and clinical implicationsrdquo Pediatricsvol 115 no 6 pp 1734ndash1746 2005

[15] Y W Wong D-G Kim and J-Y Lee ldquoTraditional orientalherbal medicine for children and adolescents with ADHD asystematic reviewrdquo Evidence-Based Complementary and Alter-native Medicine vol 2012 Article ID 520198 15 pages 2012

[16] B M Rowles and R L Findling ldquoReview of pharmacother-apy options for the treatment of attention-deficithyperactivitydisorder (ADHD) and ADHD-like symptoms in children andadolescents with developmental disordersrdquoDevelopmental Dis-abilities Research Reviews vol 16 no 3 pp 273ndash282 2010

[17] D J Heal S C Cheetham and S L Smith ldquoThe neuropharma-cology of ADHD drugs in vivo insights on efficacy and safetyrdquoNeuropharmacology vol 57 no 7-8 pp 608ndash618 2009

[18] J Lee N Grizenko V Bhat S Sengupta A Polotskaia andR Joober ldquoRelation between therapeutic response and sideeffects induced by methylphenidate as observed by parentsand teachers of children with ADHDrdquo BMC Psychiatry vol 11article 70 2011

[19] E Chan L A Rappaport and K J Kemper ldquoComplementaryand alternative therapies in childhood attention and hyper-activity problemsrdquo Journal of Developmental and BehavioralPediatrics vol 24 no 1 pp 4ndash8 2003

[20] T G Stubberfield J A Wray and T S Parry ldquoUtilization ofalternative therapies in attention-deficit hyperactivity disorderrdquoJournal of Paediatrics and Child Health vol 35 no 5 pp 450ndash453 1999

[21] D Sinha and D Efron ldquoComplementary and alternativemedicine use in children with attention deficit hyperactivitydisorderrdquo Journal of Paediatrics and Child Health vol 41 no1-2 pp 23ndash26 2005

[22] M C Ottolini E K Hamburger J O Loprieato et al ldquoCom-plementary and alternative medicine use among children in theWashington DC areardquo Ambulatory Pediatrics vol 1 no 2 pp122ndash125 2001

[23] U P Dave S R Dingankar V S Saxena et al ldquoAn open-labelstudy to elucidate the effects of standardized Bacopa monnieriextract in the management of symptoms of attention-deficithyperactivity disorder in childrenrdquo Advances in Mind-BodyMedicine vol 28 no 2 pp 10ndash15 2014

[24] H Uebel-von Sandersleben A Rothenberger B Albrecht L GRothenberger S Klement and N Bock ldquoGinkgo biloba extractEGb 761reg in children with ADHD preliminary findings of anopenmultilevel dose-finding studyrdquo Zeitschrift fur KindermdashundJugendpsychiatrie und Psychotherapie vol 42 no 5 pp 337ndash3472014

[25] B Salehi R Imani M R Mohammadi et al ldquoGinkgo biloba forattention-deficithyperactivity disorder in children and adoles-cents a double blind randomized controlled trialrdquo Progress in

Neuro-Psychopharmacology amp Biological Psychiatry vol 34 no1 pp 76ndash80 2010

[26] S H Lee W S Park and M H Lim ldquoClinical effects ofkorean red ginseng on attention deficit hyperactivity disorderin children an observational studyrdquo Journal ofGinsengResearchvol 35 no 2 pp 226ndash234 2011

[27] H-J Ko I Kim J-B Kim et al ldquoEffects of Korean red ginsengextract on behavior in children with symptoms of inatten-tion and hyperactivityimpulsivity a double-blind randomizedplacebo-controlled trialrdquo Journal of Child and Adolescent Psy-chopharmacology vol 24 no 9 pp 501ndash508 2014

[28] J-J Li Z-W Li S-Z Wang et al ldquoNingdong granule acomplementary and alternative therapy in the treatment ofattention deficithyperactivity disorderrdquo Psychopharmacologyvol 216 no 4 pp 501ndash509 2011

[29] S Akhondzadeh M R Mohammadi and F Momeni ldquoPassi-flora incarnata in the treatment of attention-deficit hyperactiv-ity disorder in children and adolescentsrdquoTherapy vol 2 no 4pp 609ndash614 2005

[30] J Trebaticka S Kopasova Z Hradecna et al ldquoTreatment ofADHD with French maritime pine bark extract PycnogenolregrdquoEuropean Child amp Adolescent Psychiatry vol 15 no 6 pp 329ndash335 2006

[31] Z Chovanova J Muchova M Sivonova et al ldquoEffect ofpolyphenolic extract Pycnogenolreg on the level of 8-oxoguaninein children suffering from attention deficithyperactivity disor-derrdquo Free Radical Research vol 40 no 9 pp 1003ndash1010 2006

[32] W Weber A Vander Stoep R L McCarty N S Weiss JBiederman and JMcClellan ldquoHypericumperforatum (St JohnrsquosWort) for attention-deficithyperactivity disorder in childrenand adolescents a randomized controlled trialrdquo The Journal ofthe American Medical Association vol 299 no 22 pp 2633ndash2641 2008

[33] R Razlog J Pellow and S JWhite ldquoA pilot study on the efficacyof Valeriana officinalismother tincture and Valeriana officinalis3X in the treatment of attention deficit hyperactivity disorderrdquoHealth SA Gesondheid vol 17 no 1 pp 1ndash7 2012

[34] M G Torrioli S Vernacotola L Peruzzi et al ldquoA double-blind parallel multicenter comparison of L-acetylcarnitinewith placebo on the attention deficit hyperactivity disorder infragile X syndrome boysrdquoAmerican Journal ofMedical GeneticsPart A vol 146 no 7 pp 803ndash812 2008

[35] L E Arnold A Amato H Bozzolo et al ldquoAcetyl-L-carnitine(ALC) in attention-deficithyperactivity disorder a multi-siteplacebo-controlled pilot trialrdquo Journal of Child and AdolescentPsychopharmacology vol 17 no 6 pp 791ndash801 2007

[36] A J Richardson and B K Puri ldquoA randomized double-blindplacebo-controlled study of the effects of supplementation withhighly unsaturated fatty acids on ADHD-related symptoms inchildren with specific learning difficultiesrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 26 no 2 pp233ndash239 2002

[37] L Stevens W Zhang L Peck et al ldquoEFA supplementation inchildren with inattention hyperactivity and other disruptivebehaviorsrdquo Lipids vol 38 no 10 pp 1007ndash1021 2003

[38] N Sinn and J Bryan ldquoEffect of supplementation with polyun-saturated fatty acids and micronutrients on learning andbehavior problems associated with child ADHDrdquo Journal ofDevelopmental and Behavioral Pediatrics vol 28 no 2 pp 82ndash91 2007


[39] N Sinn J Bryan and C Wilson ldquoCognitive effects of polyun-saturated fatty acids in children with attention deficit hyper-activity disorder symptoms a randomised controlled trialrdquoProstaglandins Leukotrienes and Essential Fatty Acids vol 78no 4-5 pp 311ndash326 2008

[40] I Manor A Magen D Keidar et al ldquoThe effect of phos-phatidylserine containing Omega3 fatty-acids on attention-deficit hyperactivity disorder symptoms in children a double-blind placebo-controlled trial followed by an open-label exten-sionrdquo European Psychiatry vol 27 no 5 pp 335ndash342 2012

[41] R Raz R L Carasso and S Yehuda ldquoThe influence of short-chain essential fatty acids on children with attention-deficithyperactivity disorder a double-blind placebo-controlledstudyrdquo Journal of Child and Adolescent Psychopharmacologyvol 19 no 2 pp 167ndash177 2009

[42] R G Voigt A M Llorente C L Jensen J K Fraley MC Berretta and W C Heird ldquoA randomized double-blindplacebo-controlled trial of docosahexaenoic acid supplementa-tion in children with attention-deficithyperactivity disorderrdquoThe Journal of Pediatrics vol 139 no 2 pp 189ndash196 2001

[43] S Hirayama T Hamazaki and K Terasawa ldquoEffect of docosa-hexaenoic acid-containing food administration on symptoms ofattention-deficithyperactivity disordermdasha placebo-controlleddouble-blind studyrdquo European Journal of Clinical Nutrition vol58 no 3 pp 467ndash473 2004

[44] E Konofal M Lecendreux J Deron et al ldquoEffects of ironsupplementation on attention deficit hyperactivity disorder inchildrenrdquo Pediatric Neurology vol 38 no 1 pp 20ndash26 2008

[45] M Mousain-Bosc M Roche A Polge D Pradal-Prat J Rapinand J-P Bali ldquoImprovement of neurobehavioral disorders inchildren supplemented with magnesium-vitamin B6 I Atten-tion deficit hyperactivity disordersrdquo Magnesium Research vol19 no 1 pp 46ndash52 2006

[46] M Bilici F Yıldırım S Kandil et al ldquoDouble-blindplacebo-controlled study of zinc sulfate in the treatmentof attention deficit hyperactivity disorderrdquo Progress in Neuro-Psychopharmacology amp Biological Psychiatry vol 28 no 1 pp181ndash190 2004

[47] S Akhondzadeh M-R Mohammadi and M Khademi ldquoZincsulfate as an adjunct to methylphenidate for the treatment ofattention deficit hyperactivity disorder in children a doubleblind and randomized trial [ISRCTN64132371]rdquo BMC Psychi-atry vol 4 article 9 2004

[48] L E Arnold R A Disilvestro D Bozzolo et al ldquoZincfor attention-deficithyperactivity disorder placebo-controlleddouble-blind pilot trial alone and combined with ampheta-minerdquo Journal of Child andAdolescent Psychopharmacology vol21 no 1 pp 1ndash19 2011

[49] M R Lyon J C Cline J T De Zepetnek J J Shan P Pangand C Benishin ldquoEffect of the herbal extract combinationPanax quinquefolium and Ginkgo biloba on attention-deficithyperactivity disorder a pilot studyrdquo Journal of Psychiatry ampNeuroscience vol 26 no 3 pp 221ndash228 2001

[50] M J Wang H Wei and Y Zhang ldquoClinical observation ofJingling oral liquid combined with methylphenidate in thetreatment of ADHD with transient Tic disorderrdquo ChineseTraditional Patent Medicine vol 33 no 9 pp 1638ndash1639 2011

[51] G-A Ding G-H Yu and S-F Chen ldquoAssessment on effect oftreatment for childhood hyperkinetic syndrome by combinedtherapy of yizhi mixture and ritalinrdquo Zhongguo Zhong Xi Yi JieHe Za Zhi vol 22 no 4 pp 255ndash257 2002

[52] M Dvorakova M Sivonova J Trebaticka et al ldquoThe effectof polyphenolic extract from pine bark Pycnogenolreg on thelevel of glutathione in children suffering from attention deficithyperactivity disorder (ADHD)rdquoRedox Report vol 11 no 4 pp163ndash172 2006

[53] M Dvorakova D Jezova P Blazıcek et al ldquoUrinary cat-echolamines in children with attention deficit hyperactivitydisorder (ADHD) modulation by a polyphenolic extract frompine bark (Pycnogenolreg)rdquo Nutritional Neuroscience vol 10 no3-4 pp 151ndash157 2007

[54] J Sarris J Kean I Schweitzer and J Lake ldquoComplementarymedicines (herbal and nutritional products) in the treatment ofattention deficit hyperactivity disorder (ADHD) a systematicreview of the evidencerdquo Complementary Therapies in Medicinevol 19 no 4 pp 216ndash227 2011

[55] J Sarris ldquoSt Johnrsquos wort for the treatment of psychiatricdisordersrdquoThe Psychiatric Clinics of North America vol 36 no1 pp 65ndash71 2013

[56] H Niederhofer ldquoSt Johnrsquos wort may improve some symptomsof attention-deficit hyperactivity disorderrdquo Natural ProductResearch vol 24 no 3 pp 203ndash205 2010

[57] R Knorle ldquoExtracts of Sideritis scardica as triple monoaminereuptake inhibitorsrdquo Journal of Neural Transmission vol 119 no12 pp 1477ndash1482 2012

[58] K Blum A L Chen E R Braverman et al ldquoAttention-deficit-hyperactivity disorder and reward deficiency syndromerdquo TheJournal of Neuropsychiatric Disease and Treatment vol 4 no5 pp 893ndash918 2003

[59] M Miroddi G Calapai M Navarra P L Minciullo and SGangemi ldquoPassiflora incarnata L ethnopharmacology clinicalapplication safety and evaluation of clinical trialsrdquo Journal ofEthnopharmacology vol 150 no 3 pp 791ndash804 2013

[60] S Y Yoon I C dela Pena C Y Shin et al ldquoConvulsion-relatedactivities of Scutellaria flavones are related to the 57-dihydroxylstructuresrdquo European Journal of Pharmacology vol 659 no 2-3pp 155ndash160 2011

[61] I C dela Pena S Y Yoon Y Kim et al ldquo57-Dihydroxy-6-methoxy-41015840-phenoxyflavone a derivative of oroxylin Aimproves attention-deficithyperactivity disorder (ADHD)-likebehaviors in spontaneously hypertensive ratsrdquoEuropean Journalof Pharmacology vol 715 no 1ndash3 pp 337ndash344 2013

[62] S Y Yoon I dela Pena S M Kim et al ldquoOroxylin Aimproves attention deficit hyperactivity disorder-like behaviorsin the spontaneously hypertensive rat and inhibits reuptake ofdopamine in vitrordquo Archives of Pharmacal Research vol 36 no1 pp 134ndash140 2013

[63] Y Nam E-J Shin S W Shin et al ldquoYY162 prevents ADHD-like behavioral side effects and cytotoxicity induced by Aro-clor1254 via interactive signaling between antioxidant potentialBDNFTrkBDATandNETrdquoFood andChemical Toxicology vol65 pp 280ndash292 2014

[64] W Dimpfel ldquoPharmacological classification of herbal extractsby means of comparison to spectral EEG signatures induced bysynthetic drugs in the freely moving ratrdquo Journal of Ethnophar-macology vol 149 no 2 pp 583ndash589 2013

[65] A Panossian G Wikman and J Sarris ldquoRosenroot (Rhodiolarosea) traditional use chemical composition pharmacologyand clinical efficacyrdquo Phytomedicine vol 17 no 7 pp 481ndash4932010

[66] C Ulbricht W Chao S Tanguay-Colucci et al ldquoRhodiola(Rhodiola spp) an evidence-based systematic review by the


natural standard research collaborationrdquo Alternative and Com-plementary Therapies vol 17 no 2 pp 110ndash119 2011

[67] E M G Olsson B von Scheele and A G Panossian ldquoArandomised double-blind placebo-controlled parallel-groupstudy of the standardised extract SHR-5 of the roots of Rhodiolarosea in the treatment of subjects with stress-related fatiguerdquoPlanta Medica vol 75 no 2 pp 105ndash112 2009

[68] A Bystritsky L Kerwin and J D Feusner ldquoA pilot studyof Rhodiola rosea (Rhodax) for generalized anxiety disorder(GAD)rdquo Journal of Alternative and Complementary Medicinevol 14 no 2 pp 175ndash180 2008

[69] V Darbinyan G Aslanyan E Amroyan E Gabrielyan CMalmstrom and A Panossian ldquoClinical trial of Rhodiolarosea L extract SHR-5 in the treatment of mild to moderatedepressionrdquoNordic Journal of Psychiatry vol 61 no 5 pp 343ndash348 2007

[70] Q G Chen Y S Zeng Z Q Qu et al ldquoThe effects ofRhodiola rosea extract on 5-HT level cell proliferation andquantity of neurons at cerebral hippocampus of depressive ratsrdquoPhytomedicine vol 16 no 9 pp 830ndash838 2009

[71] B J Hillhouse D S Ming C J French and G H NTowers ldquoAcetylcholine esterase inhibitors in Rhodiola roseardquoPharmaceutical Biology vol 42 no 1 pp 68ndash72 2004

[72] K Joshi S Lad M Kale et al ldquoSupplementation with flaxoil and vitamin C improves the outcome of Attention DeficitHyperactivity Disorder (ADHD)rdquo Prostaglandins Leukotrienesand Essential Fatty Acids vol 74 no 1 pp 17ndash21 2006

[73] N Joseph Y Zhang-JamesA Perl and SV Faraone ldquoOxidativestress and ADHD a meta-analysisrdquo Journal of Attention Disor-ders vol 19 no 11 pp 915ndash924 2015

[74] C K Sen S Khanna C Rink and S Roy ldquoTocotrienols theemerging face of natural vitamin ErdquoVitamins amp Hormones vol76 pp 203ndash261 2007

[75] J R Burgess L Stevens W Zhang and L Peck ldquoLong-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorderrdquoThe American Journal of ClinicalNutrition vol 71 no 1 supplement pp 327Sndash330S 2000

[76] J J Rucklidge and B J Kaplan ldquoBroad-spectrummicronutrienttreatment for attention-deficithyperactivity disorder rationaleand evidence to daterdquo CNS Drugs vol 28 no 9 pp 775ndash7852014

[77] L E Arnold ldquoTreatment alternatives for Attention-DeficitHyperactivity Disorder (ADHD)rdquo The Journal of AttentionDisorders vol 3 no 1 pp 30ndash48 1999

[78] J J Rucklidge J Johnstone and B J Kaplan ldquoNutrient sup-plementation approaches in the treatment of ADHDrdquo ExpertReview of Neurotherapeutics vol 9 no 4 pp 461ndash476 2009

[79] B Starobrat-Hermelin and T Kozielec ldquoThe effects of magne-sium physiological supplementation on hyperactivity in chil-dren with Attention Deficit Hyperactivity Disorder (ADHD)Positive response to magnesium oral loading testrdquo MagnesiumResearch vol 10 no 2 pp 149ndash156 1997

[80] H A Gordon J J Rucklidge N M Blampied and J MJohnstone ldquoClinically significant symptom reduction in chil-dren with attention-deficithyperactivity disorder treated withmicronutrients an open-label reversal design studyrdquo Journal ofChild and Adolescent Psychopharmacology vol 25 no 10 pp783ndash798 2015

[81] A L Lardner ldquoNeurobiological effects of the green tea con-stituent theanine and its potential role in the treatment ofpsychiatric and neurodegenerative disordersrdquo Nutritional Neu-roscience vol 17 no 4 pp 145ndash155 2014

[82] M H Bloch and A Qawasmi ldquoOmega-3 fatty acid supple-mentation for the treatment of children with attention-deficithyperactivity disorder symptomatology systematic review andmeta-analysisrdquo Journal of the American Academy of Child andAdolescent Psychiatry vol 50 no 10 pp 991ndash1000 2011

[83] P J Sorgi E M Hallowell H L Hutchins and B SearsldquoEffects of an open-label pilot study with high-dose EPADHAconcentrates on plasma phospholipids and behavior in childrenwith attention deficit hyperactivity disorderrdquo Nutrition Journalvol 6 article 16 2007

[84] R Raz and L Gabis ldquoEssential fatty acids and attention-deficit-hyperactivity disorder a systematic reviewrdquo DevelopmentalMedicine amp Child Neurology vol 51 no 8 pp 580ndash592 2009

[85] C M Milte N Parletta J D Buckley A M Coates R MYoung and P R C Howe ldquoEicosapentaenoic and docosahex-aenoic acids cognition and behavior in childrenwith attention-deficithyperactivity disorder a randomized controlled trialrdquoNutrition vol 28 no 6 pp 670ndash677 2012

[86] D Gillies J K Sinn S S Lad M J Leach and M JRoss ldquoPolyunsaturated fatty acids (PUFA) for attention deficithyperactivity disorder (ADHD) in children and adolescentsrdquoCochrane Database of Systematic Reviews vol 7 Article IDCD007986 2012

[87] E J Sonuga-Barke D Brandeis S Cortese et al ldquoNonphar-macological interventions for ADHD systematic review andmeta-analyses of randomized controlled trials of dietary andpsychological treatmentsrdquo The American Journal of Psychiatryvol 170 no 3 pp 275ndash289 2013

[88] P S Jensen S P Hinshaw J M Swanson et al ldquoFindings fromthe NIMH Multimodal Treatment Study of ADHD (MTA)implications and applications for primary care providersrdquoJournal of Developmental amp Behavioral Pediatrics vol 22 no1 pp 60ndash73 2001

[89] S P Hinshaw and L E Arnold ldquoAttention-deficit hyperactivitydisorder multimodal treatment and longitudinal outcome evi-dence paradox and challengerdquoWiley Interdisciplinary ReviewsCognitive Science vol 6 no 1 pp 39ndash52 2015

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Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Brain ScienceInternational Journal of

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neurodegenerative Diseases


Journal of

Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

2 Neural Plasticity

symptom management (for reviews see [9ndash11]) However asthese therapies are not widely available only a few patientscan benefit from these treatment approaches Although theyare easy to implement the need for time and professionaltherapists and also the involvement of not only the patient butalso members of the family and teachers during the courseof behavioral therapy limit the use of behavioral ADHDtherapies

ADHD has been associated with abnormalities in cat-echolaminergic function in the brain [12] The use ofmedications that increase levels of catecholamine in thebrain received widespread support as these drugs havebeen demonstrated to alleviate ADHD symptoms [12]Drugs indicated in the management of ADHD are classifiedas stimulant and nonstimulant medications [13 14] Thepredominantly used or prescribed pharmacological inter-ventions for ADHD are stimulant medications [13 14]Methylphenidate and dextroamphetamine are examples ofthese drugs which are structurally similar to endogenouscatecholamines and whose activity increases extracellulardopamine and norepinephrine levels thereby correctingthe underlying abnormalities in catecholaminergic functionsand restoring neurotransmitter imbalance [12]Nonstimulantalternatives include atomoxetine and norepinephrine spe-cific reuptake inhibitors and the antidepressants bupropionimipramine and phenelzine [15 16] Nonstimulant alterna-tives have also been reported to increase catecholamine levelsin the brain resulting in behavioral improvement Howevernonstimulant medications have been found to be inferior tostimulant treatments on efficacy endpoints [13 16 17]

While pharmacological treatments generally improveADHD symptoms for most children 20ndash30 of affectedindividuals are nonresponders or are unable to tolerateadverse side effects of these drugs [11 18] Some of the sideeffects of stimulant medications include headache insomniaand decreased appetite motor tics nausea and abdominalpain [5 15 18] Concerns over long-term exposure risks alsodiscourage parents to medicate their children with stimulantdrugs [17] Furthermore the high likelihood for dependencediversion and abuse particular to drugs classified as scheduleII (ie stimulants) limits the use of stimulant medicationsas ADHD has been also associated with increased risk ofsubstance use disorder [17]

Due to concerns over the safety and efficacy of cur-rent pharmacological ADHD interventions there has beengrowing interest in the development of alternative treatmentssuch as natural product-derived ADHD treatments includingbotanical or herbalmedicines vitamins minerals and aminoacids [9ndash11] These alternative treatments are appealing toparents who desire for more ldquonaturalrdquo interventions for theirchildren [9 10] Approximately 50 of parents of ADHDchildren used these treatments alone or in combination withother drugs or substances [19ndash22] In this study we providea descriptive review of natural product-derived ADHD treat-ments including complementary ADHD interventions suchas vitamins minerals and other nutritional supplementsreport findings of clinical trials which evaluated efficacyand safety of these interventions and discuss the poten-tial mechanism(s) by which these agents improve ADHD

symptoms The botanical agents are enumerated in Table 1and Table 2 summarizes the vitamins minerals and othernutritional supplements evaluated for ADHD treatmentFurthermore we also discuss the findings of studies whichevaluated safety and efficacy of combining botanical agentsor pharmacological ADHD treatments to treat ADHDTheseinformation are summarized in Table 3

2 Methods

Searches were made in the electronic databases PubMedPyschINFO andThe Cochrane Library for English languagearticles from 2001 up to December 1 2015 PubMed wasused to search ADHD search terms in combination withparticular natural product-derived treatments The searchstrategy employed included combining these keywords ldquonat-ural productsrdquo ldquoplantrdquo ldquovitaminsrdquo ldquomineralsrdquo ldquoessentialfatty acidsrdquo ldquoamino acidsrdquo ldquocombination natural prod-uctsrdquo or ldquocombination with methylphenidaterdquo and ldquoADHDrdquoor ldquoattention-deficithyperactivity disorderrdquo This processyielded 671 papers covering a wide range of research articletypes As we were interested only in natural product-derivedADHD treatments which were evaluated in clinical trials weconcentrated on open-label randomized controlled trials aswell as observational studies Moreover the inclusion crite-ria included samples consisting of children and adolescentADHD patients (below 18 years of age) as well as samplesize ge 10 The number of English language articles that werereviewed for this paper was 30

3 Results

31 Pycnogenolreg (French Maritime Pine Bark Extract) Pyc-nogenol is a standardized extract derived from the bark ofthe French maritime pine (Pinus pinaster) This extract isrich in catechin phenolic acids procyanidins and taxifolineach with multiple biologic effects [30 31] Several studieson Pycnogenol showed its potentiality in improving ADHDsymptoms in patients Most notably a double-blind placebo-controlled trial with 61 participants (ages 6ndash14 years) reportedthat Pycnogenol treatment (1mgkgday) for 1 month alle-viated ADHD symptoms particularly episodic hyperactivityand inattentiveness and improved visual-motor coordina-tion [30] One month after termination of Pycnogenol therewas a relapse of symptoms in ADHD participants The latterstudy also assumed that Pycnogenolrsquos therapeutic benefitswere mediated via an increase in nitric oxide productionwhich modulates dopamine and norepinephrine release andintake [30] Pycnogenol reportedly producedmild side effectssuch as gastric discomfort Nevertheless the relatively smallnumber of participants treatedwith Pycnogenol and the shortduration of the study limit the generalization of the studyrsquosfindings It is noteworthy however that significant effectsof Pycnogenol were observed coupled with minimal sideeffects supporting the suggestion that it could be used as analternative ADHD treatment [30]

Another randomized placebo-controlled study inves-tigating efficacy of Pycnogenol reported improvement inattention along with reduction in oxidative DNA damage

Neural Plasticity 3


gsafetyandeffi

cacy

ofbo

tanicalagentsfor

ADHD

Stud

yBo

tanicalagent

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Davee

tal[23]

Bacopa

(Bacopamonnieri)

Standardized

Bacopa

monnieriextract(SBM

E)(225

mgday)for

6mon

ths

Open-labelstudy

31child

ren

6ndash12years

oldwith

ADHD

Redu

ctionof

ADHD

symptom

s(restlessness

poor

self-control

inattention

impu

lsivity

etc)

Neuroprotectio

nregu

lationof

dopamine

andinhibitio

nof

cholinesterase


Mild

gastrointestinal

sidee

ffects

Uebel-

von

Sand

ersle

benetal

[24]

Ginkgo

biloba

Ginkgo(EGb761reg)

240m

gdailygiven

for3

to5weeks

Openclinicalpilo

tstudy

20child

renwith

ADHD

Improvem

ento

fADHD

core

symptom

sIm

provem

entin

cerebrovascularb

lood

flow

reversalof

5-HT1

andno

radrenergic

receptor

redu

ctions

Reverseinh

ibition

ofMAO

-AandMAO

-B

Very

lowrateso

fmild

adversee

ventsd

uring

observationalp

eriod

Salehi

etal[25]

Ginkgo

biloba

Ginkgo

biloba

(80ndash

120m

gday)

ormethylphenidate

(20ndash

30mgday)for

6weeks

Rand

omized

doub

le-blin

dcontrolled

trial

50child

ren

6ndash14years

oldwith

ADHD

(119899=25Ginkgo

biloba

versus119899=25

methylphenidate)

Improvem

ento

fADHD

symptom

sLesseffectiv

ethan

methylphenidate

Lesser

sidee

ffects

(headacheinsomnia

andlossof

appetite)than

methylphenidate

Leee

tal[26]

Ginseng

Korean

redginseng

(1000

mgb

id)a

ndplacebotwicea

dayfor8

weeks

Observatio

nalstudy

18child

ren

6ndash14years

oldwith

ADHD

Improvem

entin

attention

Noo

tropice

ffecton

CNS

Increaseddo

paminea

ndno

repineph

rinelevels

Neuroprotectiv

eeffects

Taste

aversio

nand

repu

lsion

toginseng

Koetal[27]

Ginseng

Korean

redginseng

extract(1g

KRG

extractp

ouch)twicea

day

for8

weeks

Rand

omized

doub

le-blin

dplacebo-

controlledtrial

70child

ren

6ndash15years

oldwith

ADHD(119899=33

KRGversus119899=37

placebo)

Improvem

ento

fhyperactivity

and

inattentionsymptom

sDecreased

quantitative

electro

enceph

alograph

ythetabetaratio

Norepo

rted

adverse

events

sidee

ffects

Lietal[28]

Ningdong

Ningdon

g(5mgkgday)

versus

methylphenidate

(1mgkgday)for8

weeks

Rand

omized

doub

le-blin

dmethylphenidate-

controlled

trial

72child

ren

6ndash13years

oldwith

ADHD(119899=36

Ningdon

gversus119899=36

methylphenidate)

Similare

fficacy

tocontrol

(methylphenidate)

Regu

lationof

dopamine

byincreasin

gHVA

concentrationin

thes

era

Hypersomnia

Akh

ondzadeh

etal

[29]

Passion

flowe

rPa

ssiflora

incarnata

Dou

ble-blind

rand

omized

methylphenidate-

controlledclinical

trial

34child

renwith

ADHD

Improvem

ento

fADHD

symptom

sNot

specified

Decreased

appetitea

ndanxietynervou

sness

comparedwith

methylphenidategrou

p

4 Neural Plasticity

Table1Con

tinued

Stud

yBo

tanicalagent

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Trebaticka

etal

[30]

Pycnogenol


orplacebotre

atmentfor

4weeks

Rand

omized

doub

le-blin


dy

61child

ren

6ndash14

years

oldwith

ADHD(119899=44

Pycnogenolversus

119899=17placebo)

Attenu

ationof

hyperactivity

and

improvem

ento

fattention

visual-m

otoric

coordinatio

nand

concentration

Influ

ence

oncatecholam

ineformation

ormetabolism

Increasedprod

uctio

nof

nitricoxidew

hich

mod

ulates

dopamine

andno

repineph

rine

releasea

ndintake

Mild

sidee

ffects

inclu

ding

slownessand

gastric

discom

fort

Chovanovae

tal

[31]

Pycnogenol


orplacebotre

atmentfor

4weeks

Rand

omized

doub

le-blin


dy

61ou

tpatient

child

ren

6ndash14yearso

ldwith

ADHD(119899

=un

specified

Pycnogenolversus

placebo)

Improved

attention

redu

ctionin

oxidative

damage

Antioxidant

prop

ertie

sNorepo

rted

adverse

events

sidee

ffects

Weber

etal[32]

StJohnrsquos

wort

Rand

omized

doub

le-blin


dy

56child

ren

6ndash17years

oldwith

ADHD(119899=27

SJW

versus119899=27

placebo)

Nosig

nificant

improvem

entinADHD

symptom

s

Norepo

rted

adverse

events

sidee

ffects

Razlo

getal[33]

Valer

ian(Valeriana

officin

alis)

Dou

ble-blindplacebo-


l

30child

ren

5ndash11years

oldwith

ADHD

(119899=10Va

leriana

officin

alismother

tincture(VO

MT)

or119899=103x

potencyof

VOMTversus119899=10

placebofor3

weeks)

Improvem

ento

fADHD

symptom

sinVO

MTor

3xpo

tencygrou

pin

comparis

onto

placebo

inparticularinatte

ntion

impu

lsivityand

or

hyperactivity

Inhibitio

nof

the

breakd

ownof

GABA

inthec

entralnervou

ssyste

m

Norepo

rted

adverse

events

sidee

ffects

Neural Plasticity 5


gsafetyandeffi

cacy

ofnu

trition

alsupp

lementsforA

DHD

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Torriolietal[34]

Acetyl-L-carnitin

e(LA

C)LA

C(500

mg2tim

esday)

orplacebofor12mon

ths

Rand

omized

doub

le-blin

dplacebo-

controlledparallel

multic

enterstudy

51child

ren(A

DHDand

Fragile

Xsynd

rome)

6ndash13yearso

ld(119899=24

ALC

versus119899=27

placebo)

Redu

ctionof

ADHD

symptom

sversus

Placeboon

Clinical

GlobalImpressio

nsParentalRa

ting

Mod

ulationof

neural

transm

issionby

increasin

gacetylcholine

synthesis

stim

ulatingits

releasea

ndreleaseo

fdo

pamineinthe

stria

tum

invario

usbrain

region

s

Noadversee

ventssid

eeffectsrepo

rted

Arnoldetal[35]

Acetyl-L-carnitin

e(AL

C)ALC

inweight-b

ased

doses

from

500to

1500

mgb

idor

placebofor16weeks

Multisite

parallel-g

roup

doub

le-blin

drand

omized

pilottria

l

112child

ren

5ndash12years

old(119899=53

Acetyl-L-carnitin


Acetyl-L-carnitin

esuperio

rtoplaceboin

inattentives

ubtype

Noadversee

ventssid

eeffectsrepo

rted

Richardson

and

Puri[36]

Essentialfattyacids

Highlyun

saturatedfatty

acid

(HUFA

)EP

A186m

gday

DHA480m

gday

120574-lino

lenica

cid96

mg

vitamin

E60

IUcis-lin

oleic

acid

864m

gAA42

mgand

thym

eoil8m

gor

oliveo

il(placebo

)for12weeks

Rand

omized

doub

le-blin

dplacebo-

controlledstu

dy

41child

ren

9participantswith

drew

before

thee

ndof

12-w

eekperio

d8ndash12yearso

ld(119899=15

HUFA

versus119899=14

placebo)

Attenu

ationof

ADHD

symptom

sfore

xample

inattention

hyperactivity

improvem

entin

cogn

ition

andem

otion

Influ

ence

onsig

nal

transductio

nrelevant

toneuron

alstructure

developm

entand

functio

ns

Upsetsto

machand

difficulty

swallowing

Stevense

tal[37]

Essentialfattyacids

PUFA

supp

lement

comprise

dof

480m

gDHA

80mgEP

A40m

garachido

nica

cid(A

A)

96mgGLA

and

24mg

alph

a-tocoph

erylacetateo

ran

oliveo

ilplacebofor4

mon

ths

Rand

omized

doub

le-blin

dplacebo-

controlledstu

dy

50child

ren(girlsa

ndbo

ys)119899=25PU

FAsupp

lementatio

n119899=25

placebo

Clearb

enefitfor

all

behaviorsc

haracteristic

ofADHDwas

not

observed

Treatm

enteffectsfor

cond

uctand

attentionas

wellasw

ithclinical

improvem

entsin

oppo

sitionald

efiant

behavior

Mediatio

nof

abno

rmal

neuron

alsig

nalin

gthat

results

inaberrant

behaviors

Not

specified


ble2Con

tinued

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Sinn

andBryan

[38]

Essentialfattyacids

LC-PUFA

capsules

containing

400m

gfishoil

and100m

gevening

prim

rose

oilw

ithEP

A(93m

g)D

HA(29m

g)G

LA(10m

g)and

vitamin

E(18mg)

orplaceboSix

activ

eor6

placebocapsules

perd

ayfor15weeks

Rand

omized

doub

le-blin

dcrossover


dy

132child

ren(data

availablefor

104and87

child

ren)

7ndash12yearso

ld(119899=36PU

FAsv

ersus

119899=41PU

FA+

micronu

trientsv

ersus

119899=27placebo)

Sign

ificant

treatment

effectsbasedon

parental

ratin

gof

core

ADHD

symptom

sinbo

thPU

FAgrou

psversus

placebo

Mod

ulationof

neural

cellsig

nalin

gand

neurotransmitter

processes

PUFA

swith

other

nutrientssuchas

vitC

B 3and

B 6mod

ulates

PUFArsquosrolein

the

synthesis

ofprostaglandins

and

chem

icalsimpo

rtantfor

biologicalandbrain

functio

n

Noadversee

ventssid

eeffects

Sinn

etal[39]

Essentialfattyacids

LC-PUFA

capsules

containing

400m

gfishoil

and100m

gevening

prim

rose

oilw

ithEP

A(93m

g)D

HA(29m

g)G

LA(10m

g)and

vitamin

E(18mg)

orplaceboSix

activ

eor6

placebocapsules

perd

ayfor15weeks

Rand

omizedone-w

aycrossoverplacebo-

controlledstu

dyPh

ases

1and

2


ren

with

ADHD(PUFA

versus

PUFA

+multiv

itaminsminerals

versus

placebofor15

weeks)

Phase2

119899=104

child

renwith

ADHD

(PUFA

PUFA

+multiv

itaminm

inerals

andplacebofor15

weeks)

Improved

abilityon

attentioncontroland

vocabu

lary

perfo

rmance

durin

gph

ase2

Influ

ence

onmetabolic

andneuralactiv

ities

Increasin

gdo

pamine

activ

ityin

thefrontal

lobe

Twocaseso

fnauseaa

ndon

eepisode

ofno

sebleed

Manor

etal[40

]

Essentialfattyacids

2capsules

twicea

dayof

phosph

atidylserin

e(PS

)containing

omega-3(300

mg

ofPS

and120m

gof

EPA+

DHA)o

rcellulose

capsules

asplacebofor15weeks

Rand

omized

doub

le-blin

dsin

gle-centerplacebo

-controlledtrial

200child

ren(6ndash13y

ears

old)

rand

omlyassig

ned

toPS

-omega-3capsules

orplacebo

119873=162child

ren

completed

15weeks

oftre

atment(119899=110PS

-om

ega-3119899=52

placebo)

Improvem

ento

fADHD

symptom

s(im

pulsivity

inattention

moo

dand

behavior

issue)

Maintenance

ofintegrity

ofcellmem

branes

Influ

ence

ondo

paminergica

ndcholinergics

ystems

Increasin

gom

ega-3

LC-PUFA

which

improves

behavioral

sensoryand

neurologicaldysfu

nctio

n

Mild

adversee

vent

profi

leG

Idisc

omfort

atop

icderm

atitis

nauseaticsand

hyperactivity

Raze

tal[41]

Essentialfattyacids

EFAcapsules

containing

240m

gof

linoleica

cid(LA)

60mgof

alph

a-lin

olenicacid

(ALA

)95

mgof

mineraloil

and5m

gof

a-tocoph

erol(as

anantio

xidant)2

timesday

orplacebovitC(500

mg

ascorbicacid)2

timesday

for7

weeks

Rand

omized

doub

le-blin


73child

ren

7ndash13years

old63

child

ren

completed

thes

tudy

(119899=39EF

Asupp

lement

versus

39placebo

vitamin

C)

Both

treatments

amelioratedsome

ADHDsymptom

sNo

differenceineffi

cacy

betweentre

atments

Improvem

entin


cogn

itive

functio

ns

Noadversee

ventssid

eeffectsrepo

rted

Neural Plasticity 7

Table2Con

tinued

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Voigtetal[42]

Essentialfattyacids

345m

gof

DHAperd

ay(119899=32)o

raplacebocapsule

(119899=31)for

4mon

ths

Rand

omized

doub

le-blin

dplacebo

controlledstu

dy

54child

ren6ndash

12years

old(119899=27

docosahexaenoica

cid

(DHA)v

ersus119899=27

placebo)

DHAsupp

lementatio

ndidno

tsignificantly

improveinanyob

jective

orsubjectiv

emeasure

ofADHDsymptom

s

Welltolerated

andno

adversee

ffectsw

ere

repo

rted

Hira

yamae

tal

[43]

Essentialfattyacids

DHAgrou

pferm

ented

soybeanmilk

(600

mg

DHA12

5mL3week)bread

rolls

(300

mgDHA45g

2week)

andste

amed

bread

(600

mgD

HA60g

2w

eek)

orplacebofood

scon

taining

oliveo

ilinste

adof

DHA-

rich

fishoilfor

2weeks

Rand

omized

doub

le-blin


dy

40child

renwith

ADHD

6ndash12yearso

ld(119899=20

docosahexaenoica

cid

(DHA)v

ersus119899=20

placebo)

DHAsupp

lementatio

ndidno

timprove

ADHD-related

symptom

s

Noserio

ussid

eeffects

were

repo

rted

inthe

study

Kono

faletal[44]

Iron

80mgferrou

ssulfatetablets

orplaceboon

cedaily

inthe

morning

for12weeks

Rand

omized

doub

le-blin


trial

23ADHDchild

renwith

lowserum

ferritinlevel

(lt30

ngm

L)5ndash8y

ears

old(119899=18iro

nversus

119899=5placebo)

Improvem

ento

fhyperactiveim

pulsive

andinattentive

symptom

sintheA

DHD

ratin

gscale

Iron

isac

ofactorinthe

synthesis

ofbo

thno

repineph

rinea

nddo

pamine

Minor

sidee

ffectsw

ere

repo

rtedsuchas

nausea

constip

ation

and

abdo

minalpain

Mou

sain-Bosce

tal[45]

Vitamin

B6andmagnesiu

mADHDchild

ren

magnesiu

m-vitamin

B6(M

g-B6

)regim

en(6

mgkgd

Mg06m

gkgd

vit-B

6)for

sixmon

thsC

ontro

lsdidno

treceiveM

g-B6

Openstu

dy

76child

ren(m

eanage

69y

ears13girls

and27

boys)(40

ADHD

child

renamp36

healthy

child

ren)

Attenu

ationof

hyperactivity

and

aggressiv

enessS

choo

lattentionwas

also

improved

Vitamin

B6facilitates

thep

rodu

ctionof

the

serotonin

Magnesiu

misa

nonspecific

inhibitoro

fcalcium

andNMDA

channels

Magnesiu

mcan

influ

ence

catecholam

ine

signalin

g

Norepo

rted

sidee

ffects

Bilicietal[46]

Zinc

150m

gzinc

sulfateor

150m

gsucrose(placebo)

daily

for12

weeks

Rand

omized

doub

le-blin

dparallel-g

roup


400child

ren6ndash

14years

old(119899=202zinc

versus

119899=198placebo)

Zinc

sulfatebette

rthan

placeboin

decreasin

ghyperactivity

and

impu

lsivityand


butn

otinattention

Increasedzinc

levels

necessaryforc

ognitiv

edevelopm

ent

Noserio

ussid

eeffects

repo

rtedM

etallic

taste

was

acom

mon

complaint

8 Neural Plasticity

Table2Con

tinued

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Akh

ondzadeh

etal

[47]

Zinc

Zinc

sulfate(55m

gday)

+methylphenidate

(1mgkgday)o

rsucrose

(placebo

)55m

g+

methylphenidate

(1mgkgday)for

6weeks

Rand

omized

doub

le-blin

dclinical

trial

44child

ren

5ndash11years

old(119899=22


versus119899=22

methylphenidate+

placebo)

Sign

ificantlygreater

treatmenteffects(as

per

parent

andteacher

ratin

gscales

cores)in

zinc

sulfatewith

methylphenidate

treatmento

verp

lacebo

with

methylphenidate

Zinc

regulates

dopamine

functio

nindirectly

throug

hits

actio

non

melaton

in

Nauseaa

ndmetallic

taste

werec

ommon

complaintsOverallit

was

welltolerated

Arnoldetal[48]

Zinc

Zinc

115mgday(oncea

day)

orZinc

230

mgday

(twicea

day)

orplacebo(8

weeks)am

phetam

ine

5ndash15mgdaily

(based

onthe

weight)

Durationof

experim

entw

as13

weeks

(8weeks

controlled

+5weeks

amph

etam

ine

add-on

)

Rand

omized

doub

le-blin


trial

52child

ren6ndash

14years

old(119899=20Zinc

1or

119899=8Zinc

2versus

119899=24placebo)

Noappreciable

differenceb

etweenbo

thdo

sageso

fzinca

ndplacebo

Gastro

intestinal

discom

fortrepo

rted

by1

patie

nt

Neural Plasticity 9


stratingeffi

cacy

ofcombinatio

ntherapyof

botanicalagentsa

ndherbssupp

lementswith

methylphenidatein

treatingADHD

Stud

yMetho

dsParticipants

Outcomes

Com

ments

Lyon

etal[49]

Ginkgo

biloba

andGinseng

Ginkgo

biloba

extract

(50m

g)plus

American

ginsengPa

nax

quinquefo

lium

(200

mg)

twiceday

(com

binatio

nprod

uct)

Open

pilotstudy

36child

ren

3ndash17years

oldwith

ADHD

Improvem

ento

fADHD

symptom

s(hyperactiv

ity

impu

lsivenessand

anxiety)

Five

participants

repo

rted

adversee

vents

(increasedADHD

symptom

saggressiv

enesssw

eatin

gheadacheand

tiredness)on

ly2

considered

related

tothe

study

Wangetal[50]

Jingling

oralan

dmethylphenidate

Methylphenidate

(10ndash

40mgd)

Rand

omizedblin

ded

study

119899=50ADHDchild

ren

with

transie

nttic

disorder

Sign

ificant

improvem

ent

ofADHDsymptom

sas

wellastics

Com

binatio

ntherapy

moree

ffectivethan

methylphenidatealon

ein

improvingADHD

andtic

symptom

s

Dingetal[51]

Yizhiand

methylphenidate

Rand

omized

methylphenidate-

controlled

trial

210child

renwith

hyperkineticsynd

rome

Sign

ificant

improvem

ent

inADHDsymptom

sin

thosetaking

combinatio

ntherapy

comparedto

either

given

asmon

otherapy

Yizhih

adfewer

side


eor

incombinatio

nthan

methylphenidate

Akh

ondzadeh

etal

[47]

Zinc

sulfateand

methylphenidate

Rand

omized

doub

le-blindand

methylphenidate+


44child

ren(26bo

ys18


ldwith

ADHD

Improved

parent

and

teacherratingscale

scores

fortho

sesupp

lementedwith

zinc

sulfateas

anadjunct

Side

effectsrepo

rted

anxietylossof

appetite

nauseaheadache

abdo

minalpain

insomniaandmetallic

taste



















































5 Conclusion








Acknowledgments


References












































































































Neural Plasticity










Psychiatry Journal









Journal of


Neural Plasticity 3


gsafetyandeffi

cacy

ofbo

tanicalagentsfor

ADHD

Stud

yBo

tanicalagent

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Davee

tal[23]

Bacopa

(Bacopamonnieri)

Standardized

Bacopa

monnieriextract(SBM

E)(225

mgday)for

6mon

ths

Open-labelstudy

31child

ren

6ndash12years

oldwith

ADHD

Redu

ctionof

ADHD

symptom

s(restlessness

poor

self-control

inattention

impu

lsivity

etc)

Neuroprotectio

nregu

lationof

dopamine

andinhibitio

nof

cholinesterase


Mild

gastrointestinal

sidee

ffects

Uebel-

von

Sand

ersle

benetal

[24]

Ginkgo

biloba

Ginkgo(EGb761reg)

240m

gdailygiven

for3

to5weeks

Openclinicalpilo

tstudy

20child

renwith

ADHD

Improvem

ento

fADHD

core

symptom

sIm

provem

entin

cerebrovascularb

lood

flow

reversalof

5-HT1

andno

radrenergic

receptor

redu

ctions

Reverseinh

ibition

ofMAO

-AandMAO

-B

Very

lowrateso

fmild

adversee

ventsd

uring

observationalp

eriod

Salehi

etal[25]

Ginkgo

biloba

Ginkgo

biloba

(80ndash

120m

gday)

ormethylphenidate

(20ndash

30mgday)for

6weeks

Rand

omized

doub

le-blin

dcontrolled

trial

50child

ren

6ndash14years

oldwith

ADHD

(119899=25Ginkgo

biloba

versus119899=25

methylphenidate)

Improvem

ento

fADHD

symptom

sLesseffectiv

ethan

methylphenidate

Lesser

sidee

ffects

(headacheinsomnia

andlossof

appetite)than

methylphenidate

Leee

tal[26]

Ginseng

Korean

redginseng

(1000

mgb

id)a

ndplacebotwicea

dayfor8

weeks

Observatio

nalstudy

18child

ren

6ndash14years

oldwith

ADHD

Improvem

entin

attention

Noo

tropice

ffecton

CNS

Increaseddo

paminea

ndno

repineph

rinelevels

Neuroprotectiv

eeffects

Taste

aversio

nand

repu

lsion

toginseng

Koetal[27]

Ginseng

Korean

redginseng

extract(1g

KRG

extractp

ouch)twicea

day

for8

weeks

Rand

omized

doub

le-blin

dplacebo-

controlledtrial

70child

ren

6ndash15years

oldwith

ADHD(119899=33

KRGversus119899=37

placebo)

Improvem

ento

fhyperactivity

and

inattentionsymptom

sDecreased

quantitative

electro

enceph

alograph

ythetabetaratio

Norepo

rted

adverse

events

sidee

ffects

Lietal[28]

Ningdong

Ningdon

g(5mgkgday)

versus

methylphenidate

(1mgkgday)for8

weeks

Rand

omized

doub

le-blin

dmethylphenidate-

controlled

trial

72child

ren

6ndash13years

oldwith

ADHD(119899=36

Ningdon

gversus119899=36

methylphenidate)

Similare

fficacy

tocontrol

(methylphenidate)

Regu

lationof

dopamine

byincreasin

gHVA

concentrationin

thes

era

Hypersomnia

Akh

ondzadeh

etal

[29]

Passion

flowe

rPa

ssiflora

incarnata

Dou

ble-blind

rand

omized

methylphenidate-

controlledclinical

trial

34child

renwith

ADHD

Improvem

ento

fADHD

symptom

sNot

specified

Decreased

appetitea

ndanxietynervou

sness

comparedwith

methylphenidategrou

p

4 Neural Plasticity

Table1Con

tinued

Stud

yBo

tanicalagent

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Trebaticka

etal

[30]

Pycnogenol


orplacebotre

atmentfor

4weeks

Rand

omized

doub

le-blin


dy

61child

ren

6ndash14

years

oldwith

ADHD(119899=44

Pycnogenolversus

119899=17placebo)

Attenu

ationof

hyperactivity

and

improvem

ento

fattention

visual-m

otoric

coordinatio

nand

concentration

Influ

ence

oncatecholam

ineformation

ormetabolism

Increasedprod

uctio

nof

nitricoxidew

hich

mod

ulates

dopamine

andno

repineph

rine

releasea

ndintake

Mild

sidee

ffects

inclu

ding

slownessand

gastric

discom

fort

Chovanovae

tal

[31]

Pycnogenol


orplacebotre

atmentfor

4weeks

Rand

omized

doub

le-blin


dy

61ou

tpatient

child

ren

6ndash14yearso

ldwith

ADHD(119899

=un

specified

Pycnogenolversus

placebo)

Improved

attention

redu

ctionin

oxidative

damage

Antioxidant

prop

ertie

sNorepo

rted

adverse

events

sidee

ffects

Weber

etal[32]

StJohnrsquos

wort

Rand

omized

doub

le-blin


dy

56child

ren

6ndash17years

oldwith

ADHD(119899=27

SJW

versus119899=27

placebo)

Nosig

nificant

improvem

entinADHD

symptom

s

Norepo

rted

adverse

events

sidee

ffects

Razlo

getal[33]

Valer

ian(Valeriana

officin

alis)

Dou

ble-blindplacebo-


l

30child

ren

5ndash11years

oldwith

ADHD

(119899=10Va

leriana

officin

alismother

tincture(VO

MT)

or119899=103x

potencyof

VOMTversus119899=10

placebofor3

weeks)

Improvem

ento

fADHD

symptom

sinVO

MTor

3xpo

tencygrou

pin

comparis

onto

placebo

inparticularinatte

ntion

impu

lsivityand

or

hyperactivity

Inhibitio

nof

the

breakd

ownof

GABA

inthec

entralnervou

ssyste

m

Norepo

rted

adverse

events

sidee

ffects

Neural Plasticity 5


gsafetyandeffi

cacy

ofnu

trition

alsupp

lementsforA

DHD

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Torriolietal[34]

Acetyl-L-carnitin

e(LA

C)LA

C(500

mg2tim

esday)

orplacebofor12mon

ths

Rand

omized

doub

le-blin

dplacebo-

controlledparallel

multic

enterstudy

51child

ren(A

DHDand

Fragile

Xsynd

rome)

6ndash13yearso

ld(119899=24

ALC

versus119899=27

placebo)

Redu

ctionof

ADHD

symptom

sversus

Placeboon

Clinical

GlobalImpressio

nsParentalRa

ting

Mod

ulationof

neural

transm

issionby

increasin

gacetylcholine

synthesis

stim

ulatingits

releasea

ndreleaseo

fdo

pamineinthe

stria

tum

invario

usbrain

region

s

Noadversee

ventssid

eeffectsrepo

rted

Arnoldetal[35]

Acetyl-L-carnitin

e(AL

C)ALC

inweight-b

ased

doses

from

500to

1500

mgb

idor

placebofor16weeks

Multisite

parallel-g

roup

doub

le-blin

drand

omized

pilottria

l

112child

ren

5ndash12years

old(119899=53

Acetyl-L-carnitin


Acetyl-L-carnitin

esuperio

rtoplaceboin

inattentives

ubtype

Noadversee

ventssid

eeffectsrepo

rted

Richardson

and

Puri[36]

Essentialfattyacids

Highlyun

saturatedfatty

acid

(HUFA

)EP

A186m

gday

DHA480m

gday

120574-lino

lenica

cid96

mg

vitamin

E60

IUcis-lin

oleic

acid

864m

gAA42

mgand

thym

eoil8m

gor

oliveo

il(placebo

)for12weeks

Rand

omized

doub

le-blin

dplacebo-

controlledstu

dy

41child

ren

9participantswith

drew

before

thee

ndof

12-w

eekperio

d8ndash12yearso

ld(119899=15

HUFA

versus119899=14

placebo)

Attenu

ationof

ADHD

symptom

sfore

xample

inattention

hyperactivity

improvem

entin

cogn

ition

andem

otion

Influ

ence

onsig

nal

transductio

nrelevant

toneuron

alstructure

developm

entand

functio

ns

Upsetsto

machand

difficulty

swallowing

Stevense

tal[37]

Essentialfattyacids

PUFA

supp

lement

comprise

dof

480m

gDHA

80mgEP

A40m

garachido

nica

cid(A

A)

96mgGLA

and

24mg

alph

a-tocoph

erylacetateo

ran

oliveo

ilplacebofor4

mon

ths

Rand

omized

doub

le-blin

dplacebo-

controlledstu

dy

50child

ren(girlsa

ndbo

ys)119899=25PU

FAsupp

lementatio

n119899=25

placebo

Clearb

enefitfor

all

behaviorsc

haracteristic

ofADHDwas

not

observed

Treatm

enteffectsfor

cond

uctand

attentionas

wellasw

ithclinical

improvem

entsin

oppo

sitionald

efiant

behavior

Mediatio

nof

abno

rmal

neuron

alsig

nalin

gthat

results

inaberrant

behaviors

Not

specified


ble2Con

tinued

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Sinn

andBryan

[38]

Essentialfattyacids

LC-PUFA

capsules

containing

400m

gfishoil

and100m

gevening

prim

rose

oilw

ithEP

A(93m

g)D

HA(29m

g)G

LA(10m

g)and

vitamin

E(18mg)

orplaceboSix

activ

eor6

placebocapsules

perd

ayfor15weeks

Rand

omized

doub

le-blin

dcrossover


dy

132child

ren(data

availablefor

104and87

child

ren)

7ndash12yearso

ld(119899=36PU

FAsv

ersus

119899=41PU

FA+

micronu

trientsv

ersus

119899=27placebo)

Sign

ificant

treatment

effectsbasedon

parental

ratin

gof

core

ADHD

symptom

sinbo

thPU

FAgrou

psversus

placebo

Mod

ulationof

neural

cellsig

nalin

gand

neurotransmitter

processes

PUFA

swith

other

nutrientssuchas

vitC

B 3and

B 6mod

ulates

PUFArsquosrolein

the

synthesis

ofprostaglandins

and

chem

icalsimpo

rtantfor

biologicalandbrain

functio

n

Noadversee

ventssid

eeffects

Sinn

etal[39]

Essentialfattyacids

LC-PUFA

capsules

containing

400m

gfishoil

and100m

gevening

prim

rose

oilw

ithEP

A(93m

g)D

HA(29m

g)G

LA(10m

g)and

vitamin

E(18mg)

orplaceboSix

activ

eor6

placebocapsules

perd

ayfor15weeks

Rand

omizedone-w

aycrossoverplacebo-

controlledstu

dyPh

ases

1and

2


ren

with

ADHD(PUFA

versus

PUFA

+multiv

itaminsminerals

versus

placebofor15

weeks)

Phase2

119899=104

child

renwith

ADHD

(PUFA

PUFA

+multiv

itaminm

inerals

andplacebofor15

weeks)

Improved

abilityon

attentioncontroland

vocabu

lary

perfo

rmance

durin

gph

ase2

Influ

ence

onmetabolic

andneuralactiv

ities

Increasin

gdo

pamine

activ

ityin

thefrontal

lobe

Twocaseso

fnauseaa

ndon

eepisode

ofno

sebleed

Manor

etal[40

]

Essentialfattyacids

2capsules

twicea

dayof

phosph

atidylserin

e(PS

)containing

omega-3(300

mg

ofPS

and120m

gof

EPA+

DHA)o

rcellulose

capsules

asplacebofor15weeks

Rand

omized

doub

le-blin

dsin

gle-centerplacebo

-controlledtrial

200child

ren(6ndash13y

ears

old)

rand

omlyassig

ned

toPS

-omega-3capsules

orplacebo

119873=162child

ren

completed

15weeks

oftre

atment(119899=110PS

-om

ega-3119899=52

placebo)

Improvem

ento

fADHD

symptom

s(im

pulsivity

inattention

moo

dand

behavior

issue)

Maintenance

ofintegrity

ofcellmem

branes

Influ

ence

ondo

paminergica

ndcholinergics

ystems

Increasin

gom

ega-3

LC-PUFA

which

improves

behavioral

sensoryand

neurologicaldysfu

nctio

n

Mild

adversee

vent

profi

leG

Idisc

omfort

atop

icderm

atitis

nauseaticsand

hyperactivity

Raze

tal[41]

Essentialfattyacids

EFAcapsules

containing

240m

gof

linoleica

cid(LA)

60mgof

alph

a-lin

olenicacid

(ALA

)95

mgof

mineraloil

and5m

gof

a-tocoph

erol(as

anantio

xidant)2

timesday

orplacebovitC(500

mg

ascorbicacid)2

timesday

for7

weeks

Rand

omized

doub

le-blin


73child

ren

7ndash13years

old63

child

ren

completed

thes

tudy

(119899=39EF

Asupp

lement

versus

39placebo

vitamin

C)

Both

treatments

amelioratedsome

ADHDsymptom

sNo

differenceineffi

cacy

betweentre

atments

Improvem

entin


cogn

itive

functio

ns

Noadversee

ventssid

eeffectsrepo

rted

Neural Plasticity 7

Table2Con

tinued

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Voigtetal[42]

Essentialfattyacids

345m

gof

DHAperd

ay(119899=32)o

raplacebocapsule

(119899=31)for

4mon

ths

Rand

omized

doub

le-blin

dplacebo

controlledstu

dy

54child

ren6ndash

12years

old(119899=27

docosahexaenoica

cid

(DHA)v

ersus119899=27

placebo)

DHAsupp

lementatio

ndidno

tsignificantly

improveinanyob

jective

orsubjectiv

emeasure

ofADHDsymptom

s

Welltolerated

andno

adversee

ffectsw

ere

repo

rted

Hira

yamae

tal

[43]

Essentialfattyacids

DHAgrou

pferm

ented

soybeanmilk

(600

mg

DHA12

5mL3week)bread

rolls

(300

mgDHA45g

2week)

andste

amed

bread

(600

mgD

HA60g

2w

eek)

orplacebofood

scon

taining

oliveo

ilinste

adof

DHA-

rich

fishoilfor

2weeks

Rand

omized

doub

le-blin


dy

40child

renwith

ADHD

6ndash12yearso

ld(119899=20

docosahexaenoica

cid

(DHA)v

ersus119899=20

placebo)

DHAsupp

lementatio

ndidno

timprove

ADHD-related

symptom

s

Noserio

ussid

eeffects

were

repo

rted

inthe

study

Kono

faletal[44]

Iron

80mgferrou

ssulfatetablets

orplaceboon

cedaily

inthe

morning

for12weeks

Rand

omized

doub

le-blin


trial

23ADHDchild

renwith

lowserum

ferritinlevel

(lt30

ngm

L)5ndash8y

ears

old(119899=18iro

nversus

119899=5placebo)

Improvem

ento

fhyperactiveim

pulsive

andinattentive

symptom

sintheA

DHD

ratin

gscale

Iron

isac

ofactorinthe

synthesis

ofbo

thno

repineph

rinea

nddo

pamine

Minor

sidee

ffectsw

ere

repo

rtedsuchas

nausea

constip

ation

and

abdo

minalpain

Mou

sain-Bosce

tal[45]

Vitamin

B6andmagnesiu

mADHDchild

ren

magnesiu

m-vitamin

B6(M

g-B6

)regim

en(6

mgkgd

Mg06m

gkgd

vit-B

6)for

sixmon

thsC

ontro

lsdidno

treceiveM

g-B6

Openstu

dy

76child

ren(m

eanage

69y

ears13girls

and27

boys)(40

ADHD

child

renamp36

healthy

child

ren)

Attenu

ationof

hyperactivity

and

aggressiv

enessS

choo

lattentionwas

also

improved

Vitamin

B6facilitates

thep

rodu

ctionof

the

serotonin

Magnesiu

misa

nonspecific

inhibitoro

fcalcium

andNMDA

channels

Magnesiu

mcan

influ

ence

catecholam

ine

signalin

g

Norepo

rted

sidee

ffects

Bilicietal[46]

Zinc

150m

gzinc

sulfateor

150m

gsucrose(placebo)

daily

for12

weeks

Rand

omized

doub

le-blin

dparallel-g

roup


400child

ren6ndash

14years

old(119899=202zinc

versus

119899=198placebo)

Zinc

sulfatebette

rthan

placeboin

decreasin

ghyperactivity

and

impu

lsivityand


butn

otinattention

Increasedzinc

levels

necessaryforc

ognitiv

edevelopm

ent

Noserio

ussid

eeffects

repo

rtedM

etallic

taste

was

acom

mon

complaint

8 Neural Plasticity

Table2Con

tinued

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Akh

ondzadeh

etal

[47]

Zinc

Zinc

sulfate(55m

gday)

+methylphenidate

(1mgkgday)o

rsucrose

(placebo

)55m

g+

methylphenidate

(1mgkgday)for

6weeks

Rand

omized

doub

le-blin

dclinical

trial

44child

ren

5ndash11years

old(119899=22


versus119899=22

methylphenidate+

placebo)

Sign

ificantlygreater

treatmenteffects(as

per

parent

andteacher

ratin

gscales

cores)in

zinc

sulfatewith

methylphenidate

treatmento

verp

lacebo

with

methylphenidate

Zinc

regulates

dopamine

functio

nindirectly

throug

hits

actio

non

melaton

in

Nauseaa

ndmetallic

taste

werec

ommon

complaintsOverallit

was

welltolerated

Arnoldetal[48]

Zinc

Zinc

115mgday(oncea

day)

orZinc

230

mgday

(twicea

day)

orplacebo(8

weeks)am

phetam

ine

5ndash15mgdaily

(based

onthe

weight)

Durationof

experim

entw

as13

weeks

(8weeks

controlled

+5weeks

amph

etam

ine

add-on

)

Rand

omized

doub

le-blin


trial

52child

ren6ndash

14years

old(119899=20Zinc

1or

119899=8Zinc

2versus

119899=24placebo)

Noappreciable

differenceb

etweenbo

thdo

sageso

fzinca

ndplacebo

Gastro

intestinal

discom

fortrepo

rted

by1

patie

nt

Neural Plasticity 9


stratingeffi

cacy

ofcombinatio

ntherapyof

botanicalagentsa

ndherbssupp

lementswith

methylphenidatein

treatingADHD

Stud

yMetho

dsParticipants

Outcomes

Com

ments

Lyon

etal[49]

Ginkgo

biloba

andGinseng

Ginkgo

biloba

extract

(50m

g)plus

American

ginsengPa

nax

quinquefo

lium

(200

mg)

twiceday

(com

binatio

nprod

uct)

Open

pilotstudy

36child

ren

3ndash17years

oldwith

ADHD

Improvem

ento

fADHD

symptom

s(hyperactiv

ity

impu

lsivenessand

anxiety)

Five

participants

repo

rted

adversee

vents

(increasedADHD

symptom

saggressiv

enesssw

eatin

gheadacheand

tiredness)on

ly2

considered

related

tothe

study

Wangetal[50]

Jingling

oralan

dmethylphenidate

Methylphenidate

(10ndash

40mgd)

Rand

omizedblin

ded

study

119899=50ADHDchild

ren

with

transie

nttic

disorder

Sign

ificant

improvem

ent

ofADHDsymptom

sas

wellastics

Com

binatio

ntherapy

moree

ffectivethan

methylphenidatealon

ein

improvingADHD

andtic

symptom

s

Dingetal[51]

Yizhiand

methylphenidate

Rand

omized

methylphenidate-

controlled

trial

210child

renwith

hyperkineticsynd

rome

Sign

ificant

improvem

ent

inADHDsymptom

sin

thosetaking

combinatio

ntherapy

comparedto

either

given

asmon

otherapy

Yizhih

adfewer

side


eor

incombinatio

nthan

methylphenidate

Akh

ondzadeh

etal

[47]

Zinc

sulfateand

methylphenidate

Rand

omized

doub

le-blindand

methylphenidate+


44child

ren(26bo

ys18


ldwith

ADHD

Improved

parent

and

teacherratingscale

scores

fortho

sesupp

lementedwith

zinc

sulfateas

anadjunct

Side

effectsrepo

rted

anxietylossof

appetite

nauseaheadache

abdo

minalpain

insomniaandmetallic

taste



















































5 Conclusion








Acknowledgments


References












































































































Neural Plasticity










Psychiatry Journal









Journal of


4 Neural Plasticity

Table1Con

tinued

Stud

yBo

tanicalagent

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Trebaticka

etal

[30]

Pycnogenol


orplacebotre

atmentfor

4weeks

Rand

omized

doub

le-blin


dy

61child

ren

6ndash14

years

oldwith

ADHD(119899=44

Pycnogenolversus

119899=17placebo)

Attenu

ationof

hyperactivity

and

improvem

ento

fattention

visual-m

otoric

coordinatio

nand

concentration

Influ

ence

oncatecholam

ineformation

ormetabolism

Increasedprod

uctio

nof

nitricoxidew

hich

mod

ulates

dopamine

andno

repineph

rine

releasea

ndintake

Mild

sidee

ffects

inclu

ding

slownessand

gastric

discom

fort

Chovanovae

tal

[31]

Pycnogenol


orplacebotre

atmentfor

4weeks

Rand

omized

doub

le-blin


dy

61ou

tpatient

child

ren

6ndash14yearso

ldwith

ADHD(119899

=un

specified

Pycnogenolversus

placebo)

Improved

attention

redu

ctionin

oxidative

damage

Antioxidant

prop

ertie

sNorepo

rted

adverse

events

sidee

ffects

Weber

etal[32]

StJohnrsquos

wort

Rand

omized

doub

le-blin


dy

56child

ren

6ndash17years

oldwith

ADHD(119899=27

SJW

versus119899=27

placebo)

Nosig

nificant

improvem

entinADHD

symptom

s

Norepo

rted

adverse

events

sidee

ffects

Razlo

getal[33]

Valer

ian(Valeriana

officin

alis)

Dou

ble-blindplacebo-


l

30child

ren

5ndash11years

oldwith

ADHD

(119899=10Va

leriana

officin

alismother

tincture(VO

MT)

or119899=103x

potencyof

VOMTversus119899=10

placebofor3

weeks)

Improvem

ento

fADHD

symptom

sinVO

MTor

3xpo

tencygrou

pin

comparis

onto

placebo

inparticularinatte

ntion

impu

lsivityand

or

hyperactivity

Inhibitio

nof

the

breakd

ownof

GABA

inthec

entralnervou

ssyste

m

Norepo

rted

adverse

events

sidee

ffects

Neural Plasticity 5


gsafetyandeffi

cacy

ofnu

trition

alsupp

lementsforA

DHD

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Torriolietal[34]

Acetyl-L-carnitin

e(LA

C)LA

C(500

mg2tim

esday)

orplacebofor12mon

ths

Rand

omized

doub

le-blin

dplacebo-

controlledparallel

multic

enterstudy

51child

ren(A

DHDand

Fragile

Xsynd

rome)

6ndash13yearso

ld(119899=24

ALC

versus119899=27

placebo)

Redu

ctionof

ADHD

symptom

sversus

Placeboon

Clinical

GlobalImpressio

nsParentalRa

ting

Mod

ulationof

neural

transm

issionby

increasin

gacetylcholine

synthesis

stim

ulatingits

releasea

ndreleaseo

fdo

pamineinthe

stria

tum

invario

usbrain

region

s

Noadversee

ventssid

eeffectsrepo

rted

Arnoldetal[35]

Acetyl-L-carnitin

e(AL

C)ALC

inweight-b

ased

doses

from

500to

1500

mgb

idor

placebofor16weeks

Multisite

parallel-g

roup

doub

le-blin

drand

omized

pilottria

l

112child

ren

5ndash12years

old(119899=53

Acetyl-L-carnitin


Acetyl-L-carnitin

esuperio

rtoplaceboin

inattentives

ubtype

Noadversee

ventssid

eeffectsrepo

rted

Richardson

and

Puri[36]

Essentialfattyacids

Highlyun

saturatedfatty

acid

(HUFA

)EP

A186m

gday

DHA480m

gday

120574-lino

lenica

cid96

mg

vitamin

E60

IUcis-lin

oleic

acid

864m

gAA42

mgand

thym

eoil8m

gor

oliveo

il(placebo

)for12weeks

Rand

omized

doub

le-blin

dplacebo-

controlledstu

dy

41child

ren

9participantswith

drew

before

thee

ndof

12-w

eekperio

d8ndash12yearso

ld(119899=15

HUFA

versus119899=14

placebo)

Attenu

ationof

ADHD

symptom

sfore

xample

inattention

hyperactivity

improvem

entin

cogn

ition

andem

otion

Influ

ence

onsig

nal

transductio

nrelevant

toneuron

alstructure

developm

entand

functio

ns

Upsetsto

machand

difficulty

swallowing

Stevense

tal[37]

Essentialfattyacids

PUFA

supp

lement

comprise

dof

480m

gDHA

80mgEP

A40m

garachido

nica

cid(A

A)

96mgGLA

and

24mg

alph

a-tocoph

erylacetateo

ran

oliveo

ilplacebofor4

mon

ths

Rand

omized

doub

le-blin

dplacebo-

controlledstu

dy

50child

ren(girlsa

ndbo

ys)119899=25PU

FAsupp

lementatio

n119899=25

placebo

Clearb

enefitfor

all

behaviorsc

haracteristic

ofADHDwas

not

observed

Treatm

enteffectsfor

cond

uctand

attentionas

wellasw

ithclinical

improvem

entsin

oppo

sitionald

efiant

behavior

Mediatio

nof

abno

rmal

neuron

alsig

nalin

gthat

results

inaberrant

behaviors

Not

specified


ble2Con

tinued

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Sinn

andBryan

[38]

Essentialfattyacids

LC-PUFA

capsules

containing

400m

gfishoil

and100m

gevening

prim

rose

oilw

ithEP

A(93m

g)D

HA(29m

g)G

LA(10m

g)and

vitamin

E(18mg)

orplaceboSix

activ

eor6

placebocapsules

perd

ayfor15weeks

Rand

omized

doub

le-blin

dcrossover


dy

132child

ren(data

availablefor

104and87

child

ren)

7ndash12yearso

ld(119899=36PU

FAsv

ersus

119899=41PU

FA+

micronu

trientsv

ersus

119899=27placebo)

Sign

ificant

treatment

effectsbasedon

parental

ratin

gof

core

ADHD

symptom

sinbo

thPU

FAgrou

psversus

placebo

Mod

ulationof

neural

cellsig

nalin

gand

neurotransmitter

processes

PUFA

swith

other

nutrientssuchas

vitC

B 3and

B 6mod

ulates

PUFArsquosrolein

the

synthesis

ofprostaglandins

and

chem

icalsimpo

rtantfor

biologicalandbrain

functio

n

Noadversee

ventssid

eeffects

Sinn

etal[39]

Essentialfattyacids

LC-PUFA

capsules

containing

400m

gfishoil

and100m

gevening

prim

rose

oilw

ithEP

A(93m

g)D

HA(29m

g)G

LA(10m

g)and

vitamin

E(18mg)

orplaceboSix

activ

eor6

placebocapsules

perd

ayfor15weeks

Rand

omizedone-w

aycrossoverplacebo-

controlledstu

dyPh

ases

1and

2


ren

with

ADHD(PUFA

versus

PUFA

+multiv

itaminsminerals

versus

placebofor15

weeks)

Phase2

119899=104

child

renwith

ADHD

(PUFA

PUFA

+multiv

itaminm

inerals

andplacebofor15

weeks)

Improved

abilityon

attentioncontroland

vocabu

lary

perfo

rmance

durin

gph

ase2

Influ

ence

onmetabolic

andneuralactiv

ities

Increasin

gdo

pamine

activ

ityin

thefrontal

lobe

Twocaseso

fnauseaa

ndon

eepisode

ofno

sebleed

Manor

etal[40

]

Essentialfattyacids

2capsules

twicea

dayof

phosph

atidylserin

e(PS

)containing

omega-3(300

mg

ofPS

and120m

gof

EPA+

DHA)o

rcellulose

capsules

asplacebofor15weeks

Rand

omized

doub

le-blin

dsin

gle-centerplacebo

-controlledtrial

200child

ren(6ndash13y

ears

old)

rand

omlyassig

ned

toPS

-omega-3capsules

orplacebo

119873=162child

ren

completed

15weeks

oftre

atment(119899=110PS

-om

ega-3119899=52

placebo)

Improvem

ento

fADHD

symptom

s(im

pulsivity

inattention

moo

dand

behavior

issue)

Maintenance

ofintegrity

ofcellmem

branes

Influ

ence

ondo

paminergica

ndcholinergics

ystems

Increasin

gom

ega-3

LC-PUFA

which

improves

behavioral

sensoryand

neurologicaldysfu

nctio

n

Mild

adversee

vent

profi

leG

Idisc

omfort

atop

icderm

atitis

nauseaticsand

hyperactivity

Raze

tal[41]

Essentialfattyacids

EFAcapsules

containing

240m

gof

linoleica

cid(LA)

60mgof

alph

a-lin

olenicacid

(ALA

)95

mgof

mineraloil

and5m

gof

a-tocoph

erol(as

anantio

xidant)2

timesday

orplacebovitC(500

mg

ascorbicacid)2

timesday

for7

weeks

Rand

omized

doub

le-blin


73child

ren

7ndash13years

old63

child

ren

completed

thes

tudy

(119899=39EF

Asupp

lement

versus

39placebo

vitamin

C)

Both

treatments

amelioratedsome

ADHDsymptom

sNo

differenceineffi

cacy

betweentre

atments

Improvem

entin


cogn

itive

functio

ns

Noadversee

ventssid

eeffectsrepo

rted

Neural Plasticity 7

Table2Con

tinued

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Voigtetal[42]

Essentialfattyacids

345m

gof

DHAperd

ay(119899=32)o

raplacebocapsule

(119899=31)for

4mon

ths

Rand

omized

doub

le-blin

dplacebo

controlledstu

dy

54child

ren6ndash

12years

old(119899=27

docosahexaenoica

cid

(DHA)v

ersus119899=27

placebo)

DHAsupp

lementatio

ndidno

tsignificantly

improveinanyob

jective

orsubjectiv

emeasure

ofADHDsymptom

s

Welltolerated

andno

adversee

ffectsw

ere

repo

rted

Hira

yamae

tal

[43]

Essentialfattyacids

DHAgrou

pferm

ented

soybeanmilk

(600

mg

DHA12

5mL3week)bread

rolls

(300

mgDHA45g

2week)

andste

amed

bread

(600

mgD

HA60g

2w

eek)

orplacebofood

scon

taining

oliveo

ilinste

adof

DHA-

rich

fishoilfor

2weeks

Rand

omized

doub

le-blin


dy

40child

renwith

ADHD

6ndash12yearso

ld(119899=20

docosahexaenoica

cid

(DHA)v

ersus119899=20

placebo)

DHAsupp

lementatio

ndidno

timprove

ADHD-related

symptom

s

Noserio

ussid

eeffects

were

repo

rted

inthe

study

Kono

faletal[44]

Iron

80mgferrou

ssulfatetablets

orplaceboon

cedaily

inthe

morning

for12weeks

Rand

omized

doub

le-blin


trial

23ADHDchild

renwith

lowserum

ferritinlevel

(lt30

ngm

L)5ndash8y

ears

old(119899=18iro

nversus

119899=5placebo)

Improvem

ento

fhyperactiveim

pulsive

andinattentive

symptom

sintheA

DHD

ratin

gscale

Iron

isac

ofactorinthe

synthesis

ofbo

thno

repineph

rinea

nddo

pamine

Minor

sidee

ffectsw

ere

repo

rtedsuchas

nausea

constip

ation

and

abdo

minalpain

Mou

sain-Bosce

tal[45]

Vitamin

B6andmagnesiu

mADHDchild

ren

magnesiu

m-vitamin

B6(M

g-B6

)regim

en(6

mgkgd

Mg06m

gkgd

vit-B

6)for

sixmon

thsC

ontro

lsdidno

treceiveM

g-B6

Openstu

dy

76child

ren(m

eanage

69y

ears13girls

and27

boys)(40

ADHD

child

renamp36

healthy

child

ren)

Attenu

ationof

hyperactivity

and

aggressiv

enessS

choo

lattentionwas

also

improved

Vitamin

B6facilitates

thep

rodu

ctionof

the

serotonin

Magnesiu

misa

nonspecific

inhibitoro

fcalcium

andNMDA

channels

Magnesiu

mcan

influ

ence

catecholam

ine

signalin

g

Norepo

rted

sidee

ffects

Bilicietal[46]

Zinc

150m

gzinc

sulfateor

150m

gsucrose(placebo)

daily

for12

weeks

Rand

omized

doub

le-blin

dparallel-g

roup


400child

ren6ndash

14years

old(119899=202zinc

versus

119899=198placebo)

Zinc

sulfatebette

rthan

placeboin

decreasin

ghyperactivity

and

impu

lsivityand


butn

otinattention

Increasedzinc

levels

necessaryforc

ognitiv

edevelopm

ent

Noserio

ussid

eeffects

repo

rtedM

etallic

taste

was

acom

mon

complaint

8 Neural Plasticity

Table2Con

tinued

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Akh

ondzadeh

etal

[47]

Zinc

Zinc

sulfate(55m

gday)

+methylphenidate

(1mgkgday)o

rsucrose

(placebo

)55m

g+

methylphenidate

(1mgkgday)for

6weeks

Rand

omized

doub

le-blin

dclinical

trial

44child

ren

5ndash11years

old(119899=22


versus119899=22

methylphenidate+

placebo)

Sign

ificantlygreater

treatmenteffects(as

per

parent

andteacher

ratin

gscales

cores)in

zinc

sulfatewith

methylphenidate

treatmento

verp

lacebo

with

methylphenidate

Zinc

regulates

dopamine

functio

nindirectly

throug

hits

actio

non

melaton

in

Nauseaa

ndmetallic

taste

werec

ommon

complaintsOverallit

was

welltolerated

Arnoldetal[48]

Zinc

Zinc

115mgday(oncea

day)

orZinc

230

mgday

(twicea

day)

orplacebo(8

weeks)am

phetam

ine

5ndash15mgdaily

(based

onthe

weight)

Durationof

experim

entw

as13

weeks

(8weeks

controlled

+5weeks

amph

etam

ine

add-on

)

Rand

omized

doub

le-blin


trial

52child

ren6ndash

14years

old(119899=20Zinc

1or

119899=8Zinc

2versus

119899=24placebo)

Noappreciable

differenceb

etweenbo

thdo

sageso

fzinca

ndplacebo

Gastro

intestinal

discom

fortrepo

rted

by1

patie

nt

Neural Plasticity 9


stratingeffi

cacy

ofcombinatio

ntherapyof

botanicalagentsa

ndherbssupp

lementswith

methylphenidatein

treatingADHD

Stud

yMetho

dsParticipants

Outcomes

Com

ments

Lyon

etal[49]

Ginkgo

biloba

andGinseng

Ginkgo

biloba

extract

(50m

g)plus

American

ginsengPa

nax

quinquefo

lium

(200

mg)

twiceday

(com

binatio

nprod

uct)

Open

pilotstudy

36child

ren

3ndash17years

oldwith

ADHD

Improvem

ento

fADHD

symptom

s(hyperactiv

ity

impu

lsivenessand

anxiety)

Five

participants

repo

rted

adversee

vents

(increasedADHD

symptom

saggressiv

enesssw

eatin

gheadacheand

tiredness)on

ly2

considered

related

tothe

study

Wangetal[50]

Jingling

oralan

dmethylphenidate

Methylphenidate

(10ndash

40mgd)

Rand

omizedblin

ded

study

119899=50ADHDchild

ren

with

transie

nttic

disorder

Sign

ificant

improvem

ent

ofADHDsymptom

sas

wellastics

Com

binatio

ntherapy

moree

ffectivethan

methylphenidatealon

ein

improvingADHD

andtic

symptom

s

Dingetal[51]

Yizhiand

methylphenidate

Rand

omized

methylphenidate-

controlled

trial

210child

renwith

hyperkineticsynd

rome

Sign

ificant

improvem

ent

inADHDsymptom

sin

thosetaking

combinatio

ntherapy

comparedto

either

given

asmon

otherapy

Yizhih

adfewer

side


eor

incombinatio

nthan

methylphenidate

Akh

ondzadeh

etal

[47]

Zinc

sulfateand

methylphenidate

Rand

omized

doub

le-blindand

methylphenidate+


44child

ren(26bo

ys18


ldwith

ADHD

Improved

parent

and

teacherratingscale

scores

fortho

sesupp

lementedwith

zinc

sulfateas

anadjunct

Side

effectsrepo

rted

anxietylossof

appetite

nauseaheadache

abdo

minalpain

insomniaandmetallic

taste



















































5 Conclusion








Acknowledgments


References












































































































Neural Plasticity










Psychiatry Journal









Journal of


Neural Plasticity 5


gsafetyandeffi

cacy

ofnu

trition

alsupp

lementsforA

DHD

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Torriolietal[34]

Acetyl-L-carnitin

e(LA

C)LA

C(500

mg2tim

esday)

orplacebofor12mon

ths

Rand

omized

doub

le-blin

dplacebo-

controlledparallel

multic

enterstudy

51child

ren(A

DHDand

Fragile

Xsynd

rome)

6ndash13yearso

ld(119899=24

ALC

versus119899=27

placebo)

Redu

ctionof

ADHD

symptom

sversus

Placeboon

Clinical

GlobalImpressio

nsParentalRa

ting

Mod

ulationof

neural

transm

issionby

increasin

gacetylcholine

synthesis

stim

ulatingits

releasea

ndreleaseo

fdo

pamineinthe

stria

tum

invario

usbrain

region

s

Noadversee

ventssid

eeffectsrepo

rted

Arnoldetal[35]

Acetyl-L-carnitin

e(AL

C)ALC

inweight-b

ased

doses

from

500to

1500

mgb

idor

placebofor16weeks

Multisite

parallel-g

roup

doub

le-blin

drand

omized

pilottria

l

112child

ren

5ndash12years

old(119899=53

Acetyl-L-carnitin


Acetyl-L-carnitin

esuperio

rtoplaceboin

inattentives

ubtype

Noadversee

ventssid

eeffectsrepo

rted

Richardson

and

Puri[36]

Essentialfattyacids

Highlyun

saturatedfatty

acid

(HUFA

)EP

A186m

gday

DHA480m

gday

120574-lino

lenica

cid96

mg

vitamin

E60

IUcis-lin

oleic

acid

864m

gAA42

mgand

thym

eoil8m

gor

oliveo

il(placebo

)for12weeks

Rand

omized

doub

le-blin

dplacebo-

controlledstu

dy

41child

ren

9participantswith

drew

before

thee

ndof

12-w

eekperio

d8ndash12yearso

ld(119899=15

HUFA

versus119899=14

placebo)

Attenu

ationof

ADHD

symptom

sfore

xample

inattention

hyperactivity

improvem

entin

cogn

ition

andem

otion

Influ

ence

onsig

nal

transductio

nrelevant

toneuron

alstructure

developm

entand

functio

ns

Upsetsto

machand

difficulty

swallowing

Stevense

tal[37]

Essentialfattyacids

PUFA

supp

lement

comprise

dof

480m

gDHA

80mgEP

A40m

garachido

nica

cid(A

A)

96mgGLA

and

24mg

alph

a-tocoph

erylacetateo

ran

oliveo

ilplacebofor4

mon

ths

Rand

omized

doub

le-blin

dplacebo-

controlledstu

dy

50child

ren(girlsa

ndbo

ys)119899=25PU

FAsupp

lementatio

n119899=25

placebo

Clearb

enefitfor

all

behaviorsc

haracteristic

ofADHDwas

not

observed

Treatm

enteffectsfor

cond

uctand

attentionas

wellasw

ithclinical

improvem

entsin

oppo

sitionald

efiant

behavior

Mediatio

nof

abno

rmal

neuron

alsig

nalin

gthat

results

inaberrant

behaviors

Not

specified


ble2Con

tinued

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Sinn

andBryan

[38]

Essentialfattyacids

LC-PUFA

capsules

containing

400m

gfishoil

and100m

gevening

prim

rose

oilw

ithEP

A(93m

g)D

HA(29m

g)G

LA(10m

g)and

vitamin

E(18mg)

orplaceboSix

activ

eor6

placebocapsules

perd

ayfor15weeks

Rand

omized

doub

le-blin

dcrossover


dy

132child

ren(data

availablefor

104and87

child

ren)

7ndash12yearso

ld(119899=36PU

FAsv

ersus

119899=41PU

FA+

micronu

trientsv

ersus

119899=27placebo)

Sign

ificant

treatment

effectsbasedon

parental

ratin

gof

core

ADHD

symptom

sinbo

thPU

FAgrou

psversus

placebo

Mod

ulationof

neural

cellsig

nalin

gand

neurotransmitter

processes

PUFA

swith

other

nutrientssuchas

vitC

B 3and

B 6mod

ulates

PUFArsquosrolein

the

synthesis

ofprostaglandins

and

chem

icalsimpo

rtantfor

biologicalandbrain

functio

n

Noadversee

ventssid

eeffects

Sinn

etal[39]

Essentialfattyacids

LC-PUFA

capsules

containing

400m

gfishoil

and100m

gevening

prim

rose

oilw

ithEP

A(93m

g)D

HA(29m

g)G

LA(10m

g)and

vitamin

E(18mg)

orplaceboSix

activ

eor6

placebocapsules

perd

ayfor15weeks

Rand

omizedone-w

aycrossoverplacebo-

controlledstu

dyPh

ases

1and

2


ren

with

ADHD(PUFA

versus

PUFA

+multiv

itaminsminerals

versus

placebofor15

weeks)

Phase2

119899=104

child

renwith

ADHD

(PUFA

PUFA

+multiv

itaminm

inerals

andplacebofor15

weeks)

Improved

abilityon

attentioncontroland

vocabu

lary

perfo

rmance

durin

gph

ase2

Influ

ence

onmetabolic

andneuralactiv

ities

Increasin

gdo

pamine

activ

ityin

thefrontal

lobe

Twocaseso

fnauseaa

ndon

eepisode

ofno

sebleed

Manor

etal[40

]

Essentialfattyacids

2capsules

twicea

dayof

phosph

atidylserin

e(PS

)containing

omega-3(300

mg

ofPS

and120m

gof

EPA+

DHA)o

rcellulose

capsules

asplacebofor15weeks

Rand

omized

doub

le-blin

dsin

gle-centerplacebo

-controlledtrial

200child

ren(6ndash13y

ears

old)

rand

omlyassig

ned

toPS

-omega-3capsules

orplacebo

119873=162child

ren

completed

15weeks

oftre

atment(119899=110PS

-om

ega-3119899=52

placebo)

Improvem

ento

fADHD

symptom

s(im

pulsivity

inattention

moo

dand

behavior

issue)

Maintenance

ofintegrity

ofcellmem

branes

Influ

ence

ondo

paminergica

ndcholinergics

ystems

Increasin

gom

ega-3

LC-PUFA

which

improves

behavioral

sensoryand

neurologicaldysfu

nctio

n

Mild

adversee

vent

profi

leG

Idisc

omfort

atop

icderm

atitis

nauseaticsand

hyperactivity

Raze

tal[41]

Essentialfattyacids

EFAcapsules

containing

240m

gof

linoleica

cid(LA)

60mgof

alph

a-lin

olenicacid

(ALA

)95

mgof

mineraloil

and5m

gof

a-tocoph

erol(as

anantio

xidant)2

timesday

orplacebovitC(500

mg

ascorbicacid)2

timesday

for7

weeks

Rand

omized

doub

le-blin


73child

ren

7ndash13years

old63

child

ren

completed

thes

tudy

(119899=39EF

Asupp

lement

versus

39placebo

vitamin

C)

Both

treatments

amelioratedsome

ADHDsymptom

sNo

differenceineffi

cacy

betweentre

atments

Improvem

entin


cogn

itive

functio

ns

Noadversee

ventssid

eeffectsrepo

rted

Neural Plasticity 7

Table2Con

tinued

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Voigtetal[42]

Essentialfattyacids

345m

gof

DHAperd

ay(119899=32)o

raplacebocapsule

(119899=31)for

4mon

ths

Rand

omized

doub

le-blin

dplacebo

controlledstu

dy

54child

ren6ndash

12years

old(119899=27

docosahexaenoica

cid

(DHA)v

ersus119899=27

placebo)

DHAsupp

lementatio

ndidno

tsignificantly

improveinanyob

jective

orsubjectiv

emeasure

ofADHDsymptom

s

Welltolerated

andno

adversee

ffectsw

ere

repo

rted

Hira

yamae

tal

[43]

Essentialfattyacids

DHAgrou

pferm

ented

soybeanmilk

(600

mg

DHA12

5mL3week)bread

rolls

(300

mgDHA45g

2week)

andste

amed

bread

(600

mgD

HA60g

2w

eek)

orplacebofood

scon

taining

oliveo

ilinste

adof

DHA-

rich

fishoilfor

2weeks

Rand

omized

doub

le-blin


dy

40child

renwith

ADHD

6ndash12yearso

ld(119899=20

docosahexaenoica

cid

(DHA)v

ersus119899=20

placebo)

DHAsupp

lementatio

ndidno

timprove

ADHD-related

symptom

s

Noserio

ussid

eeffects

were

repo

rted

inthe

study

Kono

faletal[44]

Iron

80mgferrou

ssulfatetablets

orplaceboon

cedaily

inthe

morning

for12weeks

Rand

omized

doub

le-blin


trial

23ADHDchild

renwith

lowserum

ferritinlevel

(lt30

ngm

L)5ndash8y

ears

old(119899=18iro

nversus

119899=5placebo)

Improvem

ento

fhyperactiveim

pulsive

andinattentive

symptom

sintheA

DHD

ratin

gscale

Iron

isac

ofactorinthe

synthesis

ofbo

thno

repineph

rinea

nddo

pamine

Minor

sidee

ffectsw

ere

repo

rtedsuchas

nausea

constip

ation

and

abdo

minalpain

Mou

sain-Bosce

tal[45]

Vitamin

B6andmagnesiu

mADHDchild

ren

magnesiu

m-vitamin

B6(M

g-B6

)regim

en(6

mgkgd

Mg06m

gkgd

vit-B

6)for

sixmon

thsC

ontro

lsdidno

treceiveM

g-B6

Openstu

dy

76child

ren(m

eanage

69y

ears13girls

and27

boys)(40

ADHD

child

renamp36

healthy

child

ren)

Attenu

ationof

hyperactivity

and

aggressiv

enessS

choo

lattentionwas

also

improved

Vitamin

B6facilitates

thep

rodu

ctionof

the

serotonin

Magnesiu

misa

nonspecific

inhibitoro

fcalcium

andNMDA

channels

Magnesiu

mcan

influ

ence

catecholam

ine

signalin

g

Norepo

rted

sidee

ffects

Bilicietal[46]

Zinc

150m

gzinc

sulfateor

150m

gsucrose(placebo)

daily

for12

weeks

Rand

omized

doub

le-blin

dparallel-g

roup


400child

ren6ndash

14years

old(119899=202zinc

versus

119899=198placebo)

Zinc

sulfatebette

rthan

placeboin

decreasin

ghyperactivity

and

impu

lsivityand


butn

otinattention

Increasedzinc

levels

necessaryforc

ognitiv

edevelopm

ent

Noserio

ussid

eeffects

repo

rtedM

etallic

taste

was

acom

mon

complaint

8 Neural Plasticity

Table2Con

tinued

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Akh

ondzadeh

etal

[47]

Zinc

Zinc

sulfate(55m

gday)

+methylphenidate

(1mgkgday)o

rsucrose

(placebo

)55m

g+

methylphenidate

(1mgkgday)for

6weeks

Rand

omized

doub

le-blin

dclinical

trial

44child

ren

5ndash11years

old(119899=22


versus119899=22

methylphenidate+

placebo)

Sign

ificantlygreater

treatmenteffects(as

per

parent

andteacher

ratin

gscales

cores)in

zinc

sulfatewith

methylphenidate

treatmento

verp

lacebo

with

methylphenidate

Zinc

regulates

dopamine

functio

nindirectly

throug

hits

actio

non

melaton

in

Nauseaa

ndmetallic

taste

werec

ommon

complaintsOverallit

was

welltolerated

Arnoldetal[48]

Zinc

Zinc

115mgday(oncea

day)

orZinc

230

mgday

(twicea

day)

orplacebo(8

weeks)am

phetam

ine

5ndash15mgdaily

(based

onthe

weight)

Durationof

experim

entw

as13

weeks

(8weeks

controlled

+5weeks

amph

etam

ine

add-on

)

Rand

omized

doub

le-blin


trial

52child

ren6ndash

14years

old(119899=20Zinc

1or

119899=8Zinc

2versus

119899=24placebo)

Noappreciable

differenceb

etweenbo

thdo

sageso

fzinca

ndplacebo

Gastro

intestinal

discom

fortrepo

rted

by1

patie

nt

Neural Plasticity 9


stratingeffi

cacy

ofcombinatio

ntherapyof

botanicalagentsa

ndherbssupp

lementswith

methylphenidatein

treatingADHD

Stud

yMetho

dsParticipants

Outcomes

Com

ments

Lyon

etal[49]

Ginkgo

biloba

andGinseng

Ginkgo

biloba

extract

(50m

g)plus

American

ginsengPa

nax

quinquefo

lium

(200

mg)

twiceday

(com

binatio

nprod

uct)

Open

pilotstudy

36child

ren

3ndash17years

oldwith

ADHD

Improvem

ento

fADHD

symptom

s(hyperactiv

ity

impu

lsivenessand

anxiety)

Five

participants

repo

rted

adversee

vents

(increasedADHD

symptom

saggressiv

enesssw

eatin

gheadacheand

tiredness)on

ly2

considered

related

tothe

study

Wangetal[50]

Jingling

oralan

dmethylphenidate

Methylphenidate

(10ndash

40mgd)

Rand

omizedblin

ded

study

119899=50ADHDchild

ren

with

transie

nttic

disorder

Sign

ificant

improvem

ent

ofADHDsymptom

sas

wellastics

Com

binatio

ntherapy

moree

ffectivethan

methylphenidatealon

ein

improvingADHD

andtic

symptom

s

Dingetal[51]

Yizhiand

methylphenidate

Rand

omized

methylphenidate-

controlled

trial

210child

renwith

hyperkineticsynd

rome

Sign

ificant

improvem

ent

inADHDsymptom

sin

thosetaking

combinatio

ntherapy

comparedto

either

given

asmon

otherapy

Yizhih

adfewer

side


eor

incombinatio

nthan

methylphenidate

Akh

ondzadeh

etal

[47]

Zinc

sulfateand

methylphenidate

Rand

omized

doub

le-blindand

methylphenidate+


44child

ren(26bo

ys18


ldwith

ADHD

Improved

parent

and

teacherratingscale

scores

fortho

sesupp

lementedwith

zinc

sulfateas

anadjunct

Side

effectsrepo

rted

anxietylossof

appetite

nauseaheadache

abdo

minalpain

insomniaandmetallic

taste



















































5 Conclusion








Acknowledgments


References












































































































Neural Plasticity










Psychiatry Journal









Journal of



ble2Con

tinued

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Sinn

andBryan

[38]

Essentialfattyacids

LC-PUFA

capsules

containing

400m

gfishoil

and100m

gevening

prim

rose

oilw

ithEP

A(93m

g)D

HA(29m

g)G

LA(10m

g)and

vitamin

E(18mg)

orplaceboSix

activ

eor6

placebocapsules

perd

ayfor15weeks

Rand

omized

doub

le-blin

dcrossover


dy

132child

ren(data

availablefor

104and87

child

ren)

7ndash12yearso

ld(119899=36PU

FAsv

ersus

119899=41PU

FA+

micronu

trientsv

ersus

119899=27placebo)

Sign

ificant

treatment

effectsbasedon

parental

ratin

gof

core

ADHD

symptom

sinbo

thPU

FAgrou

psversus

placebo

Mod

ulationof

neural

cellsig

nalin

gand

neurotransmitter

processes

PUFA

swith

other

nutrientssuchas

vitC

B 3and

B 6mod

ulates

PUFArsquosrolein

the

synthesis

ofprostaglandins

and

chem

icalsimpo

rtantfor

biologicalandbrain

functio

n

Noadversee

ventssid

eeffects

Sinn

etal[39]

Essentialfattyacids

LC-PUFA

capsules

containing

400m

gfishoil

and100m

gevening

prim

rose

oilw

ithEP

A(93m

g)D

HA(29m

g)G

LA(10m

g)and

vitamin

E(18mg)

orplaceboSix

activ

eor6

placebocapsules

perd

ayfor15weeks

Rand

omizedone-w

aycrossoverplacebo-

controlledstu

dyPh

ases

1and

2


ren

with

ADHD(PUFA

versus

PUFA

+multiv

itaminsminerals

versus

placebofor15

weeks)

Phase2

119899=104

child

renwith

ADHD

(PUFA

PUFA

+multiv

itaminm

inerals

andplacebofor15

weeks)

Improved

abilityon

attentioncontroland

vocabu

lary

perfo

rmance

durin

gph

ase2

Influ

ence

onmetabolic

andneuralactiv

ities

Increasin

gdo

pamine

activ

ityin

thefrontal

lobe

Twocaseso

fnauseaa

ndon

eepisode

ofno

sebleed

Manor

etal[40

]

Essentialfattyacids

2capsules

twicea

dayof

phosph

atidylserin

e(PS

)containing

omega-3(300

mg

ofPS

and120m

gof

EPA+

DHA)o

rcellulose

capsules

asplacebofor15weeks

Rand

omized

doub

le-blin

dsin

gle-centerplacebo

-controlledtrial

200child

ren(6ndash13y

ears

old)

rand

omlyassig

ned

toPS

-omega-3capsules

orplacebo

119873=162child

ren

completed

15weeks

oftre

atment(119899=110PS

-om

ega-3119899=52

placebo)

Improvem

ento

fADHD

symptom

s(im

pulsivity

inattention

moo

dand

behavior

issue)

Maintenance

ofintegrity

ofcellmem

branes

Influ

ence

ondo

paminergica

ndcholinergics

ystems

Increasin

gom

ega-3

LC-PUFA

which

improves

behavioral

sensoryand

neurologicaldysfu

nctio

n

Mild

adversee

vent

profi

leG

Idisc

omfort

atop

icderm

atitis

nauseaticsand

hyperactivity

Raze

tal[41]

Essentialfattyacids

EFAcapsules

containing

240m

gof

linoleica

cid(LA)

60mgof

alph

a-lin

olenicacid

(ALA

)95

mgof

mineraloil

and5m

gof

a-tocoph

erol(as

anantio

xidant)2

timesday

orplacebovitC(500

mg

ascorbicacid)2

timesday

for7

weeks

Rand

omized

doub

le-blin


73child

ren

7ndash13years

old63

child

ren

completed

thes

tudy

(119899=39EF

Asupp

lement

versus

39placebo

vitamin

C)

Both

treatments

amelioratedsome

ADHDsymptom

sNo

differenceineffi

cacy

betweentre

atments

Improvem

entin


cogn

itive

functio

ns

Noadversee

ventssid

eeffectsrepo

rted

Neural Plasticity 7

Table2Con

tinued

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Voigtetal[42]

Essentialfattyacids

345m

gof

DHAperd

ay(119899=32)o

raplacebocapsule

(119899=31)for

4mon

ths

Rand

omized

doub

le-blin

dplacebo

controlledstu

dy

54child

ren6ndash

12years

old(119899=27

docosahexaenoica

cid

(DHA)v

ersus119899=27

placebo)

DHAsupp

lementatio

ndidno

tsignificantly

improveinanyob

jective

orsubjectiv

emeasure

ofADHDsymptom

s

Welltolerated

andno

adversee

ffectsw

ere

repo

rted

Hira

yamae

tal

[43]

Essentialfattyacids

DHAgrou

pferm

ented

soybeanmilk

(600

mg

DHA12

5mL3week)bread

rolls

(300

mgDHA45g

2week)

andste

amed

bread

(600

mgD

HA60g

2w

eek)

orplacebofood

scon

taining

oliveo

ilinste

adof

DHA-

rich

fishoilfor

2weeks

Rand

omized

doub

le-blin


dy

40child

renwith

ADHD

6ndash12yearso

ld(119899=20

docosahexaenoica

cid

(DHA)v

ersus119899=20

placebo)

DHAsupp

lementatio

ndidno

timprove

ADHD-related

symptom

s

Noserio

ussid

eeffects

were

repo

rted

inthe

study

Kono

faletal[44]

Iron

80mgferrou

ssulfatetablets

orplaceboon

cedaily

inthe

morning

for12weeks

Rand

omized

doub

le-blin


trial

23ADHDchild

renwith

lowserum

ferritinlevel

(lt30

ngm

L)5ndash8y

ears

old(119899=18iro

nversus

119899=5placebo)

Improvem

ento

fhyperactiveim

pulsive

andinattentive

symptom

sintheA

DHD

ratin

gscale

Iron

isac

ofactorinthe

synthesis

ofbo

thno

repineph

rinea

nddo

pamine

Minor

sidee

ffectsw

ere

repo

rtedsuchas

nausea

constip

ation

and

abdo

minalpain

Mou

sain-Bosce

tal[45]

Vitamin

B6andmagnesiu

mADHDchild

ren

magnesiu

m-vitamin

B6(M

g-B6

)regim

en(6

mgkgd

Mg06m

gkgd

vit-B

6)for

sixmon

thsC

ontro

lsdidno

treceiveM

g-B6

Openstu

dy

76child

ren(m

eanage

69y

ears13girls

and27

boys)(40

ADHD

child

renamp36

healthy

child

ren)

Attenu

ationof

hyperactivity

and

aggressiv

enessS

choo

lattentionwas

also

improved

Vitamin

B6facilitates

thep

rodu

ctionof

the

serotonin

Magnesiu

misa

nonspecific

inhibitoro

fcalcium

andNMDA

channels

Magnesiu

mcan

influ

ence

catecholam

ine

signalin

g

Norepo

rted

sidee

ffects

Bilicietal[46]

Zinc

150m

gzinc

sulfateor

150m

gsucrose(placebo)

daily

for12

weeks

Rand

omized

doub

le-blin

dparallel-g

roup


400child

ren6ndash

14years

old(119899=202zinc

versus

119899=198placebo)

Zinc

sulfatebette

rthan

placeboin

decreasin

ghyperactivity

and

impu

lsivityand


butn

otinattention

Increasedzinc

levels

necessaryforc

ognitiv

edevelopm

ent

Noserio

ussid

eeffects

repo

rtedM

etallic

taste

was

acom

mon

complaint

8 Neural Plasticity

Table2Con

tinued

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Akh

ondzadeh

etal

[47]

Zinc

Zinc

sulfate(55m

gday)

+methylphenidate

(1mgkgday)o

rsucrose

(placebo

)55m

g+

methylphenidate

(1mgkgday)for

6weeks

Rand

omized

doub

le-blin

dclinical

trial

44child

ren

5ndash11years

old(119899=22


versus119899=22

methylphenidate+

placebo)

Sign

ificantlygreater

treatmenteffects(as

per

parent

andteacher

ratin

gscales

cores)in

zinc

sulfatewith

methylphenidate

treatmento

verp

lacebo

with

methylphenidate

Zinc

regulates

dopamine

functio

nindirectly

throug

hits

actio

non

melaton

in

Nauseaa

ndmetallic

taste

werec

ommon

complaintsOverallit

was

welltolerated

Arnoldetal[48]

Zinc

Zinc

115mgday(oncea

day)

orZinc

230

mgday

(twicea

day)

orplacebo(8

weeks)am

phetam

ine

5ndash15mgdaily

(based

onthe

weight)

Durationof

experim

entw

as13

weeks

(8weeks

controlled

+5weeks

amph

etam

ine

add-on

)

Rand

omized

doub

le-blin


trial

52child

ren6ndash

14years

old(119899=20Zinc

1or

119899=8Zinc

2versus

119899=24placebo)

Noappreciable

differenceb

etweenbo

thdo

sageso

fzinca

ndplacebo

Gastro

intestinal

discom

fortrepo

rted

by1

patie

nt

Neural Plasticity 9


stratingeffi

cacy

ofcombinatio

ntherapyof

botanicalagentsa

ndherbssupp

lementswith

methylphenidatein

treatingADHD

Stud

yMetho

dsParticipants

Outcomes

Com

ments

Lyon

etal[49]

Ginkgo

biloba

andGinseng

Ginkgo

biloba

extract

(50m

g)plus

American

ginsengPa

nax

quinquefo

lium

(200

mg)

twiceday

(com

binatio

nprod

uct)

Open

pilotstudy

36child

ren

3ndash17years

oldwith

ADHD

Improvem

ento

fADHD

symptom

s(hyperactiv

ity

impu

lsivenessand

anxiety)

Five

participants

repo

rted

adversee

vents

(increasedADHD

symptom

saggressiv

enesssw

eatin

gheadacheand

tiredness)on

ly2

considered

related

tothe

study

Wangetal[50]

Jingling

oralan

dmethylphenidate

Methylphenidate

(10ndash

40mgd)

Rand

omizedblin

ded

study

119899=50ADHDchild

ren

with

transie

nttic

disorder

Sign

ificant

improvem

ent

ofADHDsymptom

sas

wellastics

Com

binatio

ntherapy

moree

ffectivethan

methylphenidatealon

ein

improvingADHD

andtic

symptom

s

Dingetal[51]

Yizhiand

methylphenidate

Rand

omized

methylphenidate-

controlled

trial

210child

renwith

hyperkineticsynd

rome

Sign

ificant

improvem

ent

inADHDsymptom

sin

thosetaking

combinatio

ntherapy

comparedto

either

given

asmon

otherapy

Yizhih

adfewer

side


eor

incombinatio

nthan

methylphenidate

Akh

ondzadeh

etal

[47]

Zinc

sulfateand

methylphenidate

Rand

omized

doub

le-blindand

methylphenidate+


44child

ren(26bo

ys18


ldwith

ADHD

Improved

parent

and

teacherratingscale

scores

fortho

sesupp

lementedwith

zinc

sulfateas

anadjunct

Side

effectsrepo

rted

anxietylossof

appetite

nauseaheadache

abdo

minalpain

insomniaandmetallic

taste



















































5 Conclusion








Acknowledgments


References












































































































Neural Plasticity










Psychiatry Journal









Journal of


Neural Plasticity 7

Table2Con

tinued

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Voigtetal[42]

Essentialfattyacids

345m

gof

DHAperd

ay(119899=32)o

raplacebocapsule

(119899=31)for

4mon

ths

Rand

omized

doub

le-blin

dplacebo

controlledstu

dy

54child

ren6ndash

12years

old(119899=27

docosahexaenoica

cid

(DHA)v

ersus119899=27

placebo)

DHAsupp

lementatio

ndidno

tsignificantly

improveinanyob

jective

orsubjectiv

emeasure

ofADHDsymptom

s

Welltolerated

andno

adversee

ffectsw

ere

repo

rted

Hira

yamae

tal

[43]

Essentialfattyacids

DHAgrou

pferm

ented

soybeanmilk

(600

mg

DHA12

5mL3week)bread

rolls

(300

mgDHA45g

2week)

andste

amed

bread

(600

mgD

HA60g

2w

eek)

orplacebofood

scon

taining

oliveo

ilinste

adof

DHA-

rich

fishoilfor

2weeks

Rand

omized

doub

le-blin


dy

40child

renwith

ADHD

6ndash12yearso

ld(119899=20

docosahexaenoica

cid

(DHA)v

ersus119899=20

placebo)

DHAsupp

lementatio

ndidno

timprove

ADHD-related

symptom

s

Noserio

ussid

eeffects

were

repo

rted

inthe

study

Kono

faletal[44]

Iron

80mgferrou

ssulfatetablets

orplaceboon

cedaily

inthe

morning

for12weeks

Rand

omized

doub

le-blin


trial

23ADHDchild

renwith

lowserum

ferritinlevel

(lt30

ngm

L)5ndash8y

ears

old(119899=18iro

nversus

119899=5placebo)

Improvem

ento

fhyperactiveim

pulsive

andinattentive

symptom

sintheA

DHD

ratin

gscale

Iron

isac

ofactorinthe

synthesis

ofbo

thno

repineph

rinea

nddo

pamine

Minor

sidee

ffectsw

ere

repo

rtedsuchas

nausea

constip

ation

and

abdo

minalpain

Mou

sain-Bosce

tal[45]

Vitamin

B6andmagnesiu

mADHDchild

ren

magnesiu

m-vitamin

B6(M

g-B6

)regim

en(6

mgkgd

Mg06m

gkgd

vit-B

6)for

sixmon

thsC

ontro

lsdidno

treceiveM

g-B6

Openstu

dy

76child

ren(m

eanage

69y

ears13girls

and27

boys)(40

ADHD

child

renamp36

healthy

child

ren)

Attenu

ationof

hyperactivity

and

aggressiv

enessS

choo

lattentionwas

also

improved

Vitamin

B6facilitates

thep

rodu

ctionof

the

serotonin

Magnesiu

misa

nonspecific

inhibitoro

fcalcium

andNMDA

channels

Magnesiu

mcan

influ

ence

catecholam

ine

signalin

g

Norepo

rted

sidee

ffects

Bilicietal[46]

Zinc

150m

gzinc

sulfateor

150m

gsucrose(placebo)

daily

for12

weeks

Rand

omized

doub

le-blin

dparallel-g

roup


400child

ren6ndash

14years

old(119899=202zinc

versus

119899=198placebo)

Zinc

sulfatebette

rthan

placeboin

decreasin

ghyperactivity

and

impu

lsivityand


butn

otinattention

Increasedzinc

levels

necessaryforc

ognitiv

edevelopm

ent

Noserio

ussid

eeffects

repo

rtedM

etallic

taste

was

acom

mon

complaint

8 Neural Plasticity

Table2Con

tinued

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Akh

ondzadeh

etal

[47]

Zinc

Zinc

sulfate(55m

gday)

+methylphenidate

(1mgkgday)o

rsucrose

(placebo

)55m

g+

methylphenidate

(1mgkgday)for

6weeks

Rand

omized

doub

le-blin

dclinical

trial

44child

ren

5ndash11years

old(119899=22


versus119899=22

methylphenidate+

placebo)

Sign

ificantlygreater

treatmenteffects(as

per

parent

andteacher

ratin

gscales

cores)in

zinc

sulfatewith

methylphenidate

treatmento

verp

lacebo

with

methylphenidate

Zinc

regulates

dopamine

functio

nindirectly

throug

hits

actio

non

melaton

in

Nauseaa

ndmetallic

taste

werec

ommon

complaintsOverallit

was

welltolerated

Arnoldetal[48]

Zinc

Zinc

115mgday(oncea

day)

orZinc

230

mgday

(twicea

day)

orplacebo(8

weeks)am

phetam

ine

5ndash15mgdaily

(based

onthe

weight)

Durationof

experim

entw

as13

weeks

(8weeks

controlled

+5weeks

amph

etam

ine

add-on

)

Rand

omized

doub

le-blin


trial

52child

ren6ndash

14years

old(119899=20Zinc

1or

119899=8Zinc

2versus

119899=24placebo)

Noappreciable

differenceb

etweenbo

thdo

sageso

fzinca

ndplacebo

Gastro

intestinal

discom

fortrepo

rted

by1

patie

nt

Neural Plasticity 9


stratingeffi

cacy

ofcombinatio

ntherapyof

botanicalagentsa

ndherbssupp

lementswith

methylphenidatein

treatingADHD

Stud

yMetho

dsParticipants

Outcomes

Com

ments

Lyon

etal[49]

Ginkgo

biloba

andGinseng

Ginkgo

biloba

extract

(50m

g)plus

American

ginsengPa

nax

quinquefo

lium

(200

mg)

twiceday

(com

binatio

nprod

uct)

Open

pilotstudy

36child

ren

3ndash17years

oldwith

ADHD

Improvem

ento

fADHD

symptom

s(hyperactiv

ity

impu

lsivenessand

anxiety)

Five

participants

repo

rted

adversee

vents

(increasedADHD

symptom

saggressiv

enesssw

eatin

gheadacheand

tiredness)on

ly2

considered

related

tothe

study

Wangetal[50]

Jingling

oralan

dmethylphenidate

Methylphenidate

(10ndash

40mgd)

Rand

omizedblin

ded

study

119899=50ADHDchild

ren

with

transie

nttic

disorder

Sign

ificant

improvem

ent

ofADHDsymptom

sas

wellastics

Com

binatio

ntherapy

moree

ffectivethan

methylphenidatealon

ein

improvingADHD

andtic

symptom

s

Dingetal[51]

Yizhiand

methylphenidate

Rand

omized

methylphenidate-

controlled

trial

210child

renwith

hyperkineticsynd

rome

Sign

ificant

improvem

ent

inADHDsymptom

sin

thosetaking

combinatio

ntherapy

comparedto

either

given

asmon

otherapy

Yizhih

adfewer

side


eor

incombinatio

nthan

methylphenidate

Akh

ondzadeh

etal

[47]

Zinc

sulfateand

methylphenidate

Rand

omized

doub

le-blindand

methylphenidate+


44child

ren(26bo

ys18


ldwith

ADHD

Improved

parent

and

teacherratingscale

scores

fortho

sesupp

lementedwith

zinc

sulfateas

anadjunct

Side

effectsrepo

rted

anxietylossof

appetite

nauseaheadache

abdo

minalpain

insomniaandmetallic

taste



















































5 Conclusion








Acknowledgments


References












































































































Neural Plasticity










Psychiatry Journal









Journal of


8 Neural Plasticity

Table2Con

tinued

Stud

ySupp

lement

Metho

dParticipants

Outcomes

Prop

osed

mechanism

ofactio

nCom

ments(sidee

ffects

etc)

Akh

ondzadeh

etal

[47]

Zinc

Zinc

sulfate(55m

gday)

+methylphenidate

(1mgkgday)o

rsucrose

(placebo

)55m

g+

methylphenidate

(1mgkgday)for

6weeks

Rand

omized

doub

le-blin

dclinical

trial

44child

ren

5ndash11years

old(119899=22


versus119899=22

methylphenidate+

placebo)

Sign

ificantlygreater

treatmenteffects(as

per

parent

andteacher

ratin

gscales

cores)in

zinc

sulfatewith

methylphenidate

treatmento

verp

lacebo

with

methylphenidate

Zinc

regulates

dopamine

functio

nindirectly

throug

hits

actio

non

melaton

in

Nauseaa

ndmetallic

taste

werec

ommon

complaintsOverallit

was

welltolerated

Arnoldetal[48]

Zinc

Zinc

115mgday(oncea

day)

orZinc

230

mgday

(twicea

day)

orplacebo(8

weeks)am

phetam

ine

5ndash15mgdaily

(based

onthe

weight)

Durationof

experim

entw

as13

weeks

(8weeks

controlled

+5weeks

amph

etam

ine

add-on

)

Rand

omized

doub

le-blin


trial

52child

ren6ndash

14years

old(119899=20Zinc

1or

119899=8Zinc

2versus

119899=24placebo)

Noappreciable

differenceb

etweenbo

thdo

sageso

fzinca

ndplacebo

Gastro

intestinal

discom

fortrepo

rted

by1

patie

nt

Neural Plasticity 9


stratingeffi

cacy

ofcombinatio

ntherapyof

botanicalagentsa

ndherbssupp

lementswith

methylphenidatein

treatingADHD

Stud

yMetho

dsParticipants

Outcomes

Com

ments

Lyon

etal[49]

Ginkgo

biloba

andGinseng

Ginkgo

biloba

extract

(50m

g)plus

American

ginsengPa

nax

quinquefo

lium

(200

mg)

twiceday

(com

binatio

nprod

uct)

Open

pilotstudy

36child

ren

3ndash17years

oldwith

ADHD

Improvem

ento

fADHD

symptom

s(hyperactiv

ity

impu

lsivenessand

anxiety)

Five

participants

repo

rted

adversee

vents

(increasedADHD

symptom

saggressiv

enesssw

eatin

gheadacheand

tiredness)on

ly2

considered

related

tothe

study

Wangetal[50]

Jingling

oralan

dmethylphenidate

Methylphenidate

(10ndash

40mgd)

Rand

omizedblin

ded

study

119899=50ADHDchild

ren

with

transie

nttic

disorder

Sign

ificant

improvem

ent

ofADHDsymptom

sas

wellastics

Com

binatio

ntherapy

moree

ffectivethan

methylphenidatealon

ein

improvingADHD

andtic

symptom

s

Dingetal[51]

Yizhiand

methylphenidate

Rand

omized

methylphenidate-

controlled

trial

210child

renwith

hyperkineticsynd

rome

Sign

ificant

improvem

ent

inADHDsymptom

sin

thosetaking

combinatio

ntherapy

comparedto

either

given

asmon

otherapy

Yizhih

adfewer

side


eor

incombinatio

nthan

methylphenidate

Akh

ondzadeh

etal

[47]

Zinc

sulfateand

methylphenidate

Rand

omized

doub

le-blindand

methylphenidate+


44child

ren(26bo

ys18


ldwith

ADHD

Improved

parent

and

teacherratingscale

scores

fortho

sesupp

lementedwith

zinc

sulfateas

anadjunct

Side

effectsrepo

rted

anxietylossof

appetite

nauseaheadache

abdo

minalpain

insomniaandmetallic

taste



















































5 Conclusion








Acknowledgments


References












































































































Neural Plasticity










Psychiatry Journal









Journal of


Neural Plasticity 9


stratingeffi

cacy

ofcombinatio

ntherapyof

botanicalagentsa

ndherbssupp

lementswith

methylphenidatein

treatingADHD

Stud

yMetho

dsParticipants

Outcomes

Com

ments

Lyon

etal[49]

Ginkgo

biloba

andGinseng

Ginkgo

biloba

extract

(50m

g)plus

American

ginsengPa

nax

quinquefo

lium

(200

mg)

twiceday

(com

binatio

nprod

uct)

Open

pilotstudy

36child

ren

3ndash17years

oldwith

ADHD

Improvem

ento

fADHD

symptom

s(hyperactiv

ity

impu

lsivenessand

anxiety)

Five

participants

repo

rted

adversee

vents

(increasedADHD

symptom

saggressiv

enesssw

eatin

gheadacheand

tiredness)on

ly2

considered

related

tothe

study

Wangetal[50]

Jingling

oralan

dmethylphenidate

Methylphenidate

(10ndash

40mgd)

Rand

omizedblin

ded

study

119899=50ADHDchild

ren

with

transie

nttic

disorder

Sign

ificant

improvem

ent

ofADHDsymptom

sas

wellastics

Com

binatio

ntherapy

moree

ffectivethan

methylphenidatealon

ein

improvingADHD

andtic

symptom

s

Dingetal[51]

Yizhiand

methylphenidate

Rand

omized

methylphenidate-

controlled

trial

210child

renwith

hyperkineticsynd

rome

Sign

ificant

improvem

ent

inADHDsymptom

sin

thosetaking

combinatio

ntherapy

comparedto

either

given

asmon

otherapy

Yizhih

adfewer

side


eor

incombinatio

nthan

methylphenidate

Akh

ondzadeh

etal

[47]

Zinc

sulfateand

methylphenidate

Rand

omized

doub

le-blindand

methylphenidate+


44child

ren(26bo

ys18


ldwith

ADHD

Improved

parent

and

teacherratingscale

scores

fortho

sesupp

lementedwith

zinc

sulfateas

anadjunct

Side

effectsrepo

rted

anxietylossof

appetite

nauseaheadache

abdo

minalpain

insomniaandmetallic

taste



















































5 Conclusion








Acknowledgments


References












































































































Neural Plasticity










Psychiatry Journal









Journal of




















































5 Conclusion








Acknowledgments


References












































































































Neural Plasticity










Psychiatry Journal









Journal of













































5 Conclusion








Acknowledgments


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Review Article Natural Product-Derived Treatments for ...downloads.hindawi.com/journals/np/2016/1320423.pdf · treatments) may be a promising approach to treat ADHD. e analysis indicated