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Introduction
Attention-deficit/hyperactivity disorder (ADHD) is the
most common neuropsychiatric disorder among
school-age children [8]. Children with ADHD display
as early onset of symptoms a developmentally inap-
propriate overactivity, inattention, academic under-
achievement and impulsive behaviour [2, 16].
According to a variety of epidemiological data the
incidence of ADHD in children and adolescents ranges
from 3 to 5 percent. Boys are 2.5 to 9.0 times more likely
to be diagnosed with ADHD compared to girls [1].
According to International Statistical Classification of
Diseases (ICD-10), ADHD is called Hyperkinetic Dis-
Jana Trebaticka
´
Son
ˇ
a Kopasova
´
Zuzana Hradec
ˇ
na
´
Kamil C
ˇ
inovsky
´
Igor S
ˇ
koda
´
c
ˇ
ek
Ja
´
nS
ˇ
uba
Jana Muchova
´
Ingrid Z
ˇ
itn
ˇ
anova
´
Iweta Waczulı
´
kova
´
Peter Rohdewald
Zden
ˇ
ka D
ˇ
urac
ˇ
kova
´
Treatment of ADHD with French maritime
pine bark extract, Pycnogenol
Accepted: 27 February 2006
Published online: 13 May 2006
j Abstract Attention Deficit/
Hyperactivity Disorder (ADHD) is
the most common psychiatric
disorder in children. Pycnogenol
,
an extract from the bark of the
French maritime pine, consisting
of phenolic acids, catechin, taxif-
olin and procyanidins, has shown
improvement of ADHD in case
reports and in an open study. Aim
of the present study was to evalu-
ate the effect of Pycnogenol
on
ADHD symptoms. Sixty-one chil-
dren were supplemented with
1 mg/kg/day Pycnogenol
or pla-
cebo over a period of 4 weeks in a
randomised, placebo-controlled,
doubleblind study. Patients were
examined at start of trial, 1 month
after treatment and 1 month after
end of treatment period by stan-
dard questionnaires: CAP (Child
Attention Problems) teacher rat-
ing scale, Conner’s Teacher Rating
Scale (CTRS), the Conner’s Parent
Rating Scale (CPRS) and a modi-
fied Wechsler Intelligence Scale
for children. Results show that 1-
month Pycnogenol
administra-
tion caused a significant reduction
of hyperactivity, improves atten-
tion and visual–motoric coordi-
nation and concentration of
children with ADHD. In the pla-
cebo group no positive effects
were found. One month after ter-
mination of Pycnogenol
admin-
istration a relapse of symptoms
was noted. Our results point to an
option to use Pycnogenol as a
natural supplement to relieve
ADHD symptoms of children.
j Key words inattention –
hyperactivity – ADHD –
Pycnogenol
ORIGINAL CONTRIBUTION
Eur Child Adolesc Psychiatry (2006)
15:329–335 DOI 10.1007/s00787-006-0538-3
ECAP 538
J. Trebaticka
´
(&) Æ S. Kopasova
´
Z. Hradec
ˇ
na
´
Æ K. C
ˇ
inovsky
´
I. S
ˇ
koda
´
c
ˇ
ek Æ J. S
ˇ
uba
Dept. of Child Psychiatry,
Child University Hospital
Faculty of Medicine, Comenius University
Limbova
´
1
833 40 Bratislava, Slovakia
J. Muchova
´
Æ I. Z
ˇ
itn
ˇ
anova
´
Æ Z. D
ˇ
urac
ˇ
kova
´
Institute of Medical Chemistry
Biochemistry and Clinical Biochemistry
Faculty of Medicine, Comenius University
Bratislava, Slovakia
I. Waczulı
´
kova
´
Dept. of Nuclear Physics and Biophysics
Division of Biomedical Physics
Faculty of Mathematics, Physics and
Informatics
Comenius University
Bratislava, Slovakia
P. Rohdewald
Institute of Pharmaceutical Chemistry
University of Mu
¨
nster
Mu
¨
nster, Germany
Abbreviations: BMI: body mass index;
CAP: Child Attention Problems; CPRS: The
Conner’s Parent Rating Scale; CTRS: The
Conner’s Teacher rating Scale; ICD-10:
International Statistical Classification of
Diseases and Related Health Problems;
PDW: Prague Wechsler Intelligence Scale
for children; WISC: Wechsler Intelligence
Scale for children
order. In this categorization nosological unit hyperki-
netic conduct disorder is also included.
In the pathophysiology of ADHD the dopaminergic
and noradrenergic systems are believed to play an
important role.
The primary psychopharmacotherapy for ADHD is
the prescription of stimulant medication, such as
methylphenidate or amphetamine. These drugs
modify uptake of catecholamines (dopamine, nor-
epinephrine) and thus enhance the activity of these
neurotransmitter systems, reducing symptomatology
in ADHD [13]. Recently, the nonstimulant highly
selective norepinephrine re-uptake inhibitor ato-
moxetin has become available for the treatment of
ADHD, which effectively reduces symptomatology [3,
18].
Several reports suggest a beneficial effect of Pyc-
nogenol
(Horphag Research Ltd, UK), on patients
suffering from ADHD. Pycnogenol
is a special
standardized extract from the bark of the French
maritime pine (Pinus pinaster), corresponding to the
monograph ‘‘Maritime Pine Extract of the US Phar-
macopoeia’’ [23]. This extract represents a concen-
trate of polyphenols, composed of diverse phenolic
acids, catechin, taxifolin and procyanidins with di-
verse biological and clinical effects [23].
Phenolic acids and taxifolin are rapidly absorbed
and excreted as glucuromides or sulphates, the
procyanidins, biopolymers formed from catechin or
epicatechin in subunits, are transformed inside the
intestinal tract to active metabolites (valerolactones)
[9].
First case reports about positive effects following
supplementation of ADHD children with Pycnogenol
were collected by Passwater [21]. Heimann [11] re-
ported that Pycnogenol
added to treatment with
dextroamphetamine clearly improved symptoms of
ADHD of a 10-years-old boy. Withdrawal of Pycnoge-
nol
while continuing dextroamphetamine treatment
caused a relapse, reinstated Pycnogenol
caused again
significant improvement. Positive experience with
Pycnogenol
was also reported by Hanley in her book
‘‘Attention Deficit Disorder’’ [10]. Masao published in
Japan a success rate of 70% when treating 40 children
with 1 mg/kg Pycnogenol
[17]. An attempt to dem-
onstrate reduction of ADHD symptoms in adults failed
in a double-blind, placebo-controlled, comparative
study with 24 adults [27]. No significant differences
were found between placebo, methylphenidate and
Pycnogenol
. As the study could not show a difference
between the active drug, methylphenidate, and placebo,
the relevance of these results is questionable.
In our pilot study we found a significant
improvement of ADHD symptoms after Pycnogenol
administration—1 mg/kg/day [28]. Based on these
results, our aim was to determine the effect of Pyc-
nogenol
on ADHD symptoms in children in a dou-
ble–blind, placebo-controlled study.
Materials and methods
j Patients
• Sixty one out-patients with ADHD, 50 boys and 11
girls, treated at the Dept. of Child Psychiatry of the
Child University Hospital, average age 9.5 (6–
14 years) were enrolled in a randomized, double-
blind and placebo controlled study. Patients were
randomized to receive either Pycnogenol
or pla-
cebo.
• Selection into the groups (Pycnogenol
or placebo)
was carefully randomized. Teachers, parents and
physicians were not aware of results of randomi-
zation. Randomization was done by the principal
investigator responsible for the biochemical, but,
not for clinical part. The ratio for Pycnogenol
group to placebo group was 2.5:1. The sample size
was estimated assuming the power of 80% (beta of
20%), the type one error (alpha) of 5% and the
number of controls per subject of 0.4. The recom-
mended number of patients was pre-calculated as
41 for drug investigation and 16 subjects for pla-
cebo. We included in the study 44 and 17 patients,
respectively. StatDirect
2.3.7 was used for the
randomization an unpaired random allocation to
intervention or control group and for the sample
size estimation.
• Children were included into study after evaluation
of diagnostic criteria of ADHD according to ICD-10
with following diagnoses: Hyperkinetic Disorder
(n=44), Hyperkinetic Conduct Disorder (n=11),
Attention Deficit without Hyperactivity (n=6).
Eighteen patients showed specific learning disabil-
ities additionally to these symptoms. Patient
´
s
characteristics are given in Table 1.
Inclusion criteria
Early onset of ADHD—by 6 to 7 years, chronicity—at
least 6 months of symptoms, general disposition as
restless, inattentive, distractible and disorganized.
Disorders of cognitive function: inattention, dis-
tractibility, difficulty to persist with any task, diffi-
culty in selective process to information, disturbance
of the executive functions (production, sequention
and realization of plans), disturbance of motivation,
effort and fortitude, visuospacial and memory dis-
turbance.
Disorders in control of activity: child’s inability to
suppress activity, abnormality in control of activity,
330 European Child & Adolescent Psychiatry (2006) Vol. 15, No. 6
ª Steinkopff Verlag 2006
disorganisation and discontinuation of motoric
activity.
Impulsiveness: acting without due reflection,
engaging in rash and sometimes dangerous behav-
iours, disturbances of emotions and affectivity.
Exclusion criteria
Situational hyperactivity, pervasive developmental
disorders, schizophrenia, other psychotic disorders as
mood, anxiety, personality disorder as unsocial
behaviour, personality change due to a general medical
condition, mental retardation, understimulating envi-
ronments, conduct disorder, tics, chorea and other
dyskinesias. Patients with acute inflammatory diseases,
renal and cardiovascular disorders and diabetics were
excluded from this study, too. Only somatically healthy
children were included in our study.
The study was approved by the Ethical Committee of
the Children University Hospital. Parents gave a written
consent for participation of their children in the study.
j Medication
At breakfast children received 1 mg/kg body weight/
day Pycnogenol
during 1 month or placebo with
identical shape and appearance and the same number
of tablets/day as in the case of Pycnogenol
. Placebo
contained lactose (58 mg) and cellulose (65 mg) in
tablet. Both tablets, Pycnogenol
and placebo were
produced by the same manufacturer, Drug Research
Institute, Modra, Slovakia.
During 1-month period Pycnogenol
, or placebo
tablets (equal number of pills as for Pycnogenol
) were
administered to patients. Patients were not supple-
mented with any other drugs including psychotropic
drugs or with vitamins E and C during the study.
j Methods
Patients were investigated at the beginning of the trial
before study drug administration (start 0), after
1 month of treatment (investigation period 1) and
1 month after termination of treatment (wash-out
period) (investigation period 2).
In each stage of the study patients were investi-
gated as follows:
1. Basic psychiatric examination.
2. Children were evaluated by teachers and by par-
ents using following scales:
CAP (Child Attention Problems) teacher rating
scale [5]
Conner’s Teacher rating Scale (CTRS) [4, 20]
Conner’s Parent Rating Scale (CPRS) [4, 20]
3. Psychological investigation according to pedopsy-
chiatric standard scheme of psychopathologic
phenomenon received from psychiatric interview
with Prague Wechsler Intelligence Scale for chil-
dren (PDW), a modified Wechsler Intelligence
Scale for children (WISC) standardized to our
population [14].
We applied five subtests of Performance Scale. A
Weight score was used for each subject. Weight score
is the sum of values of five subtests of the Perfor-
mance Scale, standardized for adequate age. Higher
score represents a better psychological state.
j Determination of biochemical parameters
Blood samples for biochemical analyses were taken
from venous blood at start, after treatment and after
wash-out period into commercial tubes with citrate for
determination of individual biochemical parameters.
Table 1 Basic parameters of ADHD
patients (M, male; F, female; BMI,
Body mass index: body mass (kg)/
height
2
(m
2
)
Parameters Pycnogenol group Placebo group
Included patients 44 17
Patients finishing the study 41 16
Patients who did not finished the study 3 1
Age (average) 9.5 (6–14) 8,8 (6–12)
Body mass (average) (kg) 35.28±10.13 34.80±10.05
BMI 17.41±3.13 16.77±2.61
M/F number, (M/F ratio) 37/7 (5,3:1) 13/4 (3,3:1)
Dividing of patients according medication
Patients medicated before trial, number 13 (noothropics, neuroleptics) 6 (noothropics, neuroleptics)
Patients first time investigated for ADHD 25 8
Patients non-medicated, but
under psychiatric observation
63
Dividing of patients according diagnosis
Hyperkinetic disorder 34 10
Hyperkinetic conduct disorder 5 6
Attention deficit without hyperactivity 5 1
Comorbid diagnosis
Specific learning disabilities 13 5
J. Trebaticka
´
et al. 331
ADHD and Pycnogenol
Basic biochemical parameters (bilirubin, glucose,
gamma-glutamyl transferase, alkaline phosphatase,
aspartate aminotrasferase, alanine aminotransferase,
uric acid and lipide profile) were analysed in plasma
by standard biochemical procedures using the Hitachi
911 automatic analyser (Roche, Switzerland).
j Statistical evaluation
The copies of all data obtained from questionnaires
and outputs from computerized analysers were
checked twice before their evaluation and statistical
analysis.
The effect of Pycnogenol
or placebo was evalu-
ated with one-way ANOVA for repeated measure-
ments (paired comparisons). For multiple
comparisons of treatment periods, Wilcoxon’s signed
rank test was used. The threshold P value was 0.05/
3=0.016666 (due to Bonferroni correction for triple
comparisons).
For the statistical evaluation of the differences
between boys and girls and between Pycnogenol
and
placebo groups as well, Mann–Whitney test was used
as a non-parametric analysis.
For statistical analysis we employed statistical
programmes StatsDirect
2.3.7 (StatsDirect Sales,
Sale, CHeshire M33 3UY, UK) and Statistica
6.0
(StatSoft, Inc. 2000). Graphical representation of data
was made using programmes StatsDirect and Excel
2000 (Microsoft Co.).
Results
The number of investigated patients, age, gender,
BMI, pre-study medications of patients and number
of patients who failed to complete the study are
indicated in Table 1.
From 61 patients included in the study, 57 patients
completed the study and four patients dropped out
the study, three patients from Pycnogenol group and
one patient from placebo group. Two of them decided
to discontinue their participation in our study after
the first examination, even though they received
medication. Two patients had to discontinue their
participation after the second examination, during the
wash-out period. Their questionnaires were not re-
turned. Data of all patients were evaluated according
‘‘intention-to-treat’’ analysis.
All patients were checked for any side effects. No
serious side effects were reported. We just observed
a rise of slowness in one patient and a moderate
gastritic discomfort in another one. Both patients
belonged to Pycnogenol
group and completed the
investigation. No side effects were observed in the
placebo group.
Basic biochemical parameters (bilirubin, glucose,
gamma-glutamyl transferase, alkaline phosphatase,
aspartate aminotrasferase, alanine aminotransferase,
uric acid and lipide profile) were investigated in
fasting venous blood. All values of biochemical
parameters were in the physiological range before
the trial in both groups. None of analysed bio-
chemical parameters raised or decreased beyond the
range of physiological values after 1 month of
Pycnogenol
or placebo administration.
Based on CAP and CTRS test results, teachers
evaluated inattention and hyperactivity. Parents rated
hyperactivity and inattention by CPRS tests. Psy-
chologists evaluated the Weight Score, which sums up
five subtests (see chapter ‘‘Methods’’). In the double-
blind, placebo-controlled study were evaluated all
available data of 44 patients treated with Pycnogenol
and of 17 patients receiving placebo:
CAP scores, rated by teachers, revealed no signif-
icant differences between groups at start of treatment
for hyperactivity as well as for inattention (Fig. 1).
Following 1-month of treatment with Pycnogenol
,
scores for hyperactivity (P=0.008) as well as for
inattention (P=0.00014) dropped significantly com-
0,00
5,00
10,00
210
210
Period of Investigation
Score
A
***
˚˚˚
0,00
5,00
10,00
Period of Investigation
Score
B
***
˚˚
Fig. 1 Influence of 1 month
Pycnogenol administration on
ADHD symptoms evaluated by
teachers (CAP):
– inattention (A) and
– hyperactivity (B).
empty bar—placebo group;
hatched bar—Pycnogenol group.
Significance between periods 0 and 1:
***P<0.01.
Significance for Pycnogenol versus
placebo in period 1: P<0.01,
P<0.05
332 European Child & Adolescent Psychiatry (2006) Vol. 15, No. 6
ª Steinkopff Verlag 2006
pared to start and also compared to placebo (P=0.044
and 0.0067). One month after stop of treatment,
ADHD symptoms were scored at the same level as at
start of treatment (Fig. 1).
CTRS scores for inattention, obtained from teach-
ers, differed at start considerably between groups, in
contrast to CTRS score for hyperactivity and to CAP
scores, evaluated by the same teachers. To obtain the
effect of treatment independently from starting val-
ues, CTRS scores at start for each patient were set as
the 100 percent value and changes during treatment
were calculated as percentage relative to start. With
that CTRS scoring system, teachers noted following
1 month of treatment with Pycnogenol
a marginally
significant reduction (P=0.07) of inattention com-
pared to start (Fig. 2) and compared to placebo
(P=0.049). Hyperactivity was also lower compared to
start as well as to placebo following Pycnogenol
treatment, however, the decrease failed to reach sig-
nificance level (P=0.45 and P=0.28).
ADHD symptoms evaluated by parents (CPRS)
did not significantly differ at start of treatment
between both groups. Following 1 month of Pyc-
nogenol
administration, scores for inattention
nonsignificantly decreased relative to start, also
scores for hyperactivity decreased (Fig. 3), whereas
in the placebo group no change of hyperactivity or
inattention was registered. Following 1 month of
treatment with Pycnogenol
, the lower score for
hyperactivity compared to placebo was marginally
significant (P=0.065).
The tests for visual–motoric coordination and
concentration—Weight scores—were also different
for placebo and verum group at start. Therefore,
changes under medication were evaluated as percen-
tual changes relative to start. Pycnogenol
treatment
enhanced the Weight scores significantly compared to
start (P=0.019) as well as to placebo (P=0.05), Fig. 4.
The high values 1 month after stop of treatment for
both groups point to a learning effect, giving higher
Weight scores at the 3rd session.
Discussion
The results of our double-blind, placebo-controled
study confirm the earlier reports of successful treat-
ment of ADHD of children with Pycnogenol
[17, 21].
The results reported by Tenenbaum et al. [27],
showing no treatment effect of Pycnogenol
in com-
60
80
100
120
140
210
Period of Investi
g
ation
210
Period of Investi
g
ation
Score (%)
*
A
˚˚
60
80
100
120
140
Score (%)
B
Fig. 2 Influence of 1 month
Pycnogenol administration on
ADHD symptoms evaluated
by teachers (CTRS):
– inattention (%) (A) and
– hyperactivity (%) (B)
Score at period 0=100%
empty bar—placebo group;
hatched bar—Pycnogenol group.
Significance between periods 0 and 1:
*0.1>P>0.05.
Significance for Pycnogenol versus
placebo in period 1: P<0.05
0,00
5,00
10,00
15,00
210
Period of Investigation
210
Period of Investigation
Score
˚
*
B
0,00
5,00
10,00
Score
A
Fig. 3 Influence of 1 month
Pycnogenol administration on
ADHD symptoms evaluated
by parents (CPRS):
– inattention (A) and
– hyperactivity (B)
hatched bar—Pycnogenol group;
empty bar—placebo group.
Significance between periods 0 and 1:
*0.1>P>0.05
Significance for Pycnogenol versus
placebo in period 1: 0.1>P>0.05
J. Trebaticka
´
et al. 333
ADHD and Pycnogenol
parison to placebo, are not contradictory to our
findings, because this study could not demonstrate an
effect of methylphenidate. There was no difference
between the three treatments: methylphenidate, pla-
cebo and Pycnogenol
. Whether the failure to detect
the effect of the established drug, methylphenidate,
was caused by the fact that adults had been treated or
by methodological factors, cannot be judged. How-
ever, the lack of a difference between an active drug
and placebo found by Tenenbaum et al. suggests that
the study also had not the power to detect a possible
difference between placebo and Pycnogenol
treat-
ment success.
Our findings seem to present an alternative to
treatment with existing drugs for parents fearing the
adverse effects of established drugs, however, results
of our study have to be further confirmed by studies
involving a greater number of patients.
The mechanism of the treatment success remains
to be elucidated. Analysis of urine of the patients in
our study revealed a lower excretion of catecholam-
ines compared to placebo [6], pointing to an influence
of Pycnogenol
on catecholamine formation or on
metabolism.
Another hint that Pycnogenol
influences cogni-
tive functions can be deduced from experiments with
senescence-accelerated strains of mice. These mice
loose memory and learning capabilities early in
comparison to normal mice. Feeding the senescence-
accelerated mice with Pycnogenol
restored memory
and learning dose-dependently, so that they reached
nearly the level of the control mice [15]. In a double-
blind, placebo-controlled study with elderly intake of
Pycnogeol
enhanced spatial memory [26].
It remains speculative whether these findings are
connected with an increased production of nitric
oxide, which works beside its manifold actions also as
a neurotransmitter. Pycnogenol
stimulates the
endothelial nitric oxide synthase in vitro [7] and in
vivo [25]. However, whether it also stimulates syn-
thesis of neuronal nitric oxide synthase, is not known.
Nitric oxide (NO) is involved in the regulation of
norepinephrine and dopamine release and intake
[22]. NO participates in the regulation of normal
brain functions, such as memory, learning, modula-
tion of wakefulness [29]. NO has also been proposed
to act as a neurotransmitter in the long-term poten-
tiation of synapses by traveling backward across the
synapse and enhancing the release of neurotransmit-
ter in the presynaptic neuron [24]. In fact, various
reports have indicated that NO may have a role in the
mechanism of storage and retrieval of information
[19]. The effect of NO on various types of learning has
also been examined with conflicting results [12].
In our study, teachers were able to register the de-
crease of hyperactivity and a better attention, for par-
ents, treatment success for inattention was not that
obvious. As reported by Heimann [11], the effect of
Pycnogenol
did not persist for a longer period of time.
Control after 1 month wash-out period demonstrated a
relapse of symptoms, demonstrating that Pycnogenol
has an effect on ADHD symptoms but seems not to
change the underlying fundamental processes.
During our experiments we noted that treatment
was not significantly effective for girls, in contrast to
boys. Because only six girls were in the Pycnogenol
group, we cannot judge whether we observed a true
gender-specific effect. Investigation with greater
numbers of girls is needed to see whether there is a
gender-specific effect of Pycnogenol
. The relative
small number of 44 patients treated with Pycnogenol
and the short duration of the study limits the gener-
alization of our findings. However, the small, but
significant success of treatment together with the
small incidence of mild side effects suggest that Pyc-
nogenol
could find a place as an alternative treat-
ment of ADHD of children.
j Acknowledgements This study was supported by Horphag Res.
Ltd. grant, partly by VEGA Grants No. 1/1157/04, 1/3037/06, Grant
VV MVTS 03/LF of Ministry of Education of SR, by Drug Research
Institute, Modra, SR and Mind&Health, civil association. Authors
wish to thank to Assoc. Prof. P. Blaz
ˇ
ı
´
c
ˇ
ek, PhD for the biochemical
analyses, to Mrs. L
ˇ
’. Chandogova
´
and L. Mı
´
kova
´
for their technical
assistance.
90
100
110
120
210
Period of Investi
g
ation
Score (%)
˚˚
**
Fig. 4 Influence of 1 month Pycnogenol administration on visual–motoric
coordination and concentration evaluated as Weight score (%) Score at period
0=100% empty bar—placebo group; hatched bar—Pycnogenol group.
Significance between periods 0 and 1: **P<0.05. Significance for Pycnogenol
versus placebo in period 1: P<0.05
334 European Child & Adolescent Psychiatry (2006) Vol. 15, No. 6
ª Steinkopff Verlag 2006
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