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Treatment of ADHD with French maritime pine bark extract, Pycnogenol®


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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, taxifolin and procyanidins, has shown improvement of ADHD in case reports and in an open study. Aim of the present study was to evaluate the effect of Pycnogenol on ADHD symptoms. Sixty-one children were supplemented with 1 mg/kg/day Pycnogenol or placebo 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 standard questionnaires: CAP (Child Attention Problems) teacher rating scale, Conner's Teacher Rating Scale (CTRS), the Conner's Parent Rating Scale (CPRS) and a modified Wechsler Intelligence Scale for children. Results show that 1-month Pycnogenol administration caused a significant reduction of hyperactivity, improves attention and visual-motoric coordination and concentration of children with ADHD. In the placebo group no positive effects were found. One month after termination of Pycnogenol administration 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.
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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
a Kopasova
Zuzana Hradec
Kamil C
Igor S
Jana Muchova
Ingrid Z
Iweta Waczulı
Peter Rohdewald
ka D
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
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
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
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
Eur Child Adolesc Psychiatry (2006)
15:329–335 DOI 10.1007/s00787-006-0538-3
ECAP 538
J. Trebaticka
(&) Æ S. Kopasova
Z. Hradec
Æ K. C
I. S
ek Æ J. S
Dept. of Child Psychiatry,
Child University Hospital
Faculty of Medicine, Comenius University
833 40 Bratislava, Slovakia
J. Muchova
Æ I. Z
Æ Z. D
Institute of Medical Chemistry
Biochemistry and Clinical Biochemistry
Faculty of Medicine, Comenius University
Bratislava, Slovakia
I. Waczulı
Dept. of Nuclear Physics and Biophysics
Division of Biomedical Physics
Faculty of Mathematics, Physics and
Comenius University
Bratislava, Slovakia
P. Rohdewald
Institute of Pharmaceutical Chemistry
University of 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,
Several reports suggest a benecial effect of Pyc-
(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)
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-
while continuing dextroamphetamine treatment
caused a relapse, reinstated Pycnogenol
caused again
signicant improvement. Positive experience with
was also reported by Hanley in her book
‘‘Attention Decit 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 signicant differences
were found between placebo, methylphenidate and
. 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 signicant
improvement of ADHD symptoms after Pycnogenol
administration1 mg/kg/day [28]. Based on these
results, our aim was to determine the effect of Pyc-
on ADHD symptoms in children in a dou-
bleblind, 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-
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 Decit without Hyperactivity (n=6).
Eighteen patients showed specic learning disabil-
ities additionally to these symptoms. Patient
characteristics are given in Table 1.
Inclusion criteria
Early onset of ADHDby 6 to 7 years, chronicityat
least 6 months of symptoms, general disposition as
restless, inattentive, distractible and disorganized.
Disorders of cognitive function: inattention, dis-
tractibility, difculty to persist with any task, dif-
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-
Disorders in control of activity: childs 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
Impulsiveness: acting without due reection,
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 inammatory 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]
Conners Teacher rating Scale (CTRS) [4, 20]
Conners 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 modied Wechsler Intelligence
Scale for children (WISC) standardized to our
population [14].
We applied ve subtests of Performance Scale. A
Weight score was used for each subject. Weight score
is the sum of values of ve 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)/
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 (614) 8,8 (612)
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
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 prole) 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
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, Wilcoxons signed
rank test was used. The threshold P value was 0.05/
3=0.016666 (due to Bonferroni correction for triple
For the statistical evaluation of the differences
between boys and girls and between Pycnogenol
placebo groups as well, MannWhitney 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
(StatSoft, Inc. 2000). Graphical representation of data
was made using programmes StatsDirect and Excel
2000 (Microsoft Co.).
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 rst 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 prole) 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
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
ve 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 signicantly com-
Period of Investigation
Period of Investigation
Fig. 1 Influence of 1 month
Pycnogenol administration on
ADHD symptoms evaluated by
teachers (CAP):
inattention (A) and
hyperactivity (B).
empty barplacebo group;
hatched barPycnogenol group.
Significance between periods 0 and 1:
Significance for Pycnogenol versus
placebo in period 1: P<0.01,
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
signicant 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-
nicance level (P=0.45 and P=0.28).
ADHD symptoms evaluated by parents (CPRS)
did not signicantly differ at start of treatment
between both groups. Following 1 month of Pyc-
administration, scores for inattention
nonsignicantly 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
signicant (P=0.065).
The tests for visualmotoric coordination and
concentrationWeight scoreswere also different
for placebo and verum group at start. Therefore,
changes under medication were evaluated as percen-
tual changes relative to start. Pycnogenol
enhanced the Weight scores signicantly 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.
The results of our double-blind, placebo-controled
study conrm 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-
Period of Investi
Period of Investi
Score (%)
Score (%)
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 barplacebo group;
hatched barPycnogenol group.
Significance between periods 0 and 1:
Significance for Pycnogenol versus
placebo in period 1: P<0.05
Period of Investigation
Period of Investigation
Fig. 3 Influence of 1 month
Pycnogenol administration on
ADHD symptoms evaluated
by parents (CPRS):
inattention (A) and
hyperactivity (B)
hatched barPycnogenol group;
empty barplacebo group.
Significance between periods 0 and 1:
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
ndings, 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
ment success.
Our ndings 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 conrmed 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 inuence
of Pycnogenol
on catecholamine formation or on
Another hint that Pycnogenol
inuences 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
enhanced spatial memory [26].
It remains speculative whether these ndings 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 conicting 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
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 signicantly 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-specic effect. Investigation with greater
numbers of girls is needed to see whether there is a
gender-specic 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 ndings. However, the small, but
signicant success of treatment together with the
small incidence of mild side effects suggest that Pyc-
could nd 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
ek, PhD for the biochemical
analyses, to Mrs. L
. Chandogova
and L. Mı
for their technical
Period of Investi
Score (%)
Fig. 4 Influence of 1 month Pycnogenol administration on visualmotoric
coordination and concentration evaluated as Weight score (%) Score at period
0=100% empty barplacebo group; hatched barPycnogenol 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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ADHD and Pycnogenol
... French Maritime Pine Bark Extract (PBE; Pinus Pinaster, Pycnoge-nol®, Horphag Research), a patented, proprietary commercially available extract from French maritime pine (Pinus pinaster) bark, was selected for the present study (D'Andrea, 2010;Trebatická et al., 2006). This polyphenol-rich extract, standardised to contain 70 ± 5 % procyanidins, is known for its antioxidant and anti-inflammatory properties, among other biological effects (Rohdewald, 2002). ...
... This polyphenol-rich extract, standardised to contain 70 ± 5 % procyanidins, is known for its antioxidant and anti-inflammatory properties, among other biological effects (Rohdewald, 2002). Therapeutic benefit in paediatric ADHD was suggested by a small randomised trial and observational studies (Dvoráková et al., 2006;Trebatická et al., 2006). However, its efficacy and value as compared to standard treatment with MPH were to be confirmed. ...
... • PBE reduces teacher ADHD-RS total score by 0.75 SD after 10 weeks (Pelsser et al., 2011;Trebatická et al., 2006); • Power of 80 %, dropout of 20 %; • Two-sided testing, 0.05 significance level with Bonferroni post-hoc testing correction. ...
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Objectives Determine the effect of French Maritime Pine Bark Extract (PBE; Pycnogenol®) on Attention-Deficit Hyperactivity Disorder (ADHD) behaviour and co-morbid physical/psychiatric symptoms, compared to placebo and the medicine MPH, and to assess its tolerability. Behaviour (measured by the ADHD-Rating Scale (ADHD-RS) and Social-Emotional Questionnaire (SEQ)) and physical complaints were evaluated in weeks 5 and 10. Results Eighty-eight paediatric ADHD patients (70 % male, mean age 10.1 years) were randomised to placebo (n = 30), PBE (n = 32) or MPH (n = 26). Teachers reported significant improvement of total and hyperactivity/impulsivity ADHD-RS scores by PBE and MPH after 10 weeks compared to placebo. MPH also improved inattention. SEQ ratings support ADHD-RS results. Adverse effects were reported five times more frequently for MPH than for PBE. Conclusions PBE appears a good alternative for MPH in paediatric ADHD and especially in the primary school environment, a fortiori when considering its almost complete lack of adverse effects.
... Natural products, which may be potentially used in the treatment of ADHD were presented in Table 6. American ginseng (Panax quinquefolium) in children with ADHD improved significantly on a social problems measure (Lyon et al., 2001;Trebatická et al., 2006). Another plant, Ginkgo biloba enhanced cerebrovascular blood flow and reduced hyperactivity due to the lack of focus (Nourbala and Akhoundzadeh, 2006). ...
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Neuropsychiatric diseases are a group of disorders that cause significant morbidity and disability. The symptoms of psychiatric disorders include anxiety, depression, eating disorders, autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder, and conduct disorder. Various medicinal plants are frequently used as therapeutics in traditional medicine in different parts of the world. Nowadays, using medicinal plants as an alternative medication has been considered due to their biological safety. Despite the wide range of medications, many patients are unable to tolerate the side effects and eventually lose their response. By considering the therapeutic advantages of medicinal plants in the case of side effects, patients may prefer to use them instead of chemical drugs. Today, the use of medicinal plants in traditional medicine is diverse and increasing, and these plants are a precious heritage for humanity. Investigation about traditional medicine continues, and several studies have indicated the basic pharmacology and clinical efficacy of herbal medicine. In this article, we discuss five of the most important and common psychiatric illnesses investigated in various studies along with conventional therapies and their pharmacological therapies. For this comprehensive review, data were obtained from electronic databases such as MedLine/PubMed, Science Direct, Web of Science, EMBASE, DynaMed Plus, ScienceDirect, and TRIP database. Preclinical pharmacology studies have confirmed that some bioactive compounds may have beneficial therapeutic effects in some common psychiatric disorders. The mechanisms of action of the analyzed biocompounds are presented in detail. The bioactive compounds analyzed in this review are promising phytochemicals for adjuvant and complementary drug candidates in the pharmacotherapy of neuropsychiatric diseases. Although comparative studies have been carefully reviewed in the preclinical pharmacology field, no clinical studies have been found to confirm the efficacy of herbal medicines compared to FDA-approved medicines for the treatment of mental disorders. Therefore, future clinical studies are needed to accelerate the potential use of natural compounds in the management of these diseases.
... In vitro, animal and/or human studies found PBE to have potent antioxidant and anti-inflammatory activity and to improve endothelial function, among various other effects (Grimm et al., 2004;Packer et al., 1999;Wei et al., 1997). Specifically, a previous study on ADHD patients aged 6-14 years found that treatment with 1 mg/kg/day PBE for one month improved ADHD behaviour and increased GSH levels and GSH/GSSG ratio, while there was no change in the placebo group (Dvoráková et al., 2006;Trebatická et al., 2006). However, oxidized glutathione GSSG was not measured in our present study as earlier work by our research group demonstrated that GSSG measurements were not accurate and prone to artefact GSH oxidation, resulting in GSH/GSSG ratios not reflecting real in vivo situation (Magielse et al., 2013). ...
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Objectives To evaluate the effect of French Maritime Pine Bark Extract (PBE; Pycnogenol®) on immune, oxidative stress and neurochemical biomarkers in paediatric Attention-Deficit Hyperactivity Disorder (ADHD) as compared to methylphenidate (MPH) and placebo. Results Paediatric ADHD patients (n = 88, 70 % male, mean age 10.1 years) were randomised (placebo (n = 30), PBE (n = 32) and MPH (n = 26)) receiving 20 mg/day if < 30 kg or 40 mg/day if ≥ 30 kg PBE, or 20 mg/day if < 30 kg or 30 mg/day if ≥ 30 kg MPH for 10 weeks. In the oxidative stress pathway, catalase (CAT) activity was nominally significant different in the PBE group with a p-value of 0.025 whereas the immunity biomarkers IgA and IgG2 were nominally significant different after MPH treatment with a p-value of 0.028 and 0.017 respectively, compared to baseline. Serum Neuropeptide Y (NPY) levels and weight were significantly lower after 10-weeks MPH. Conclusions Loss of appetite and weight loss was observed for MPH, whereas no differences in NPY concentrations and a significant weight gain, which is to be an expected physiological process in this age group, was noticed for PBE. Firm evidence that PBE increases antioxidant levels, reduces oxidative damage and improves immune status in general as compared to placebo or MPH could not be obtained.
... As a compound herbal remedy, M. officinalis and G. biloba were combined with Panax quinquefolius, but the results must be read more critically. Furthermore, Trebatická et al. (2006) found that minors administered pine bark isolate improved in particular teacher-rated subtests but not in parental-rated surveys. The effectiveness of C. sativus in ADHD therapy was nearly nonexistent, while the infusion findings of G. biloba and pine bark were ambiguous. ...
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Attention deficit hyperactivity disorder (ADHD) is commonly a neurodevelopmental behavioural disorder in children and adolescents. Mainly characterized by symptoms like lack of attention, hyperactivity, and impulsiveness, it can impact the overall mental development of the one affected. Several factors, both genetic and non-genetic, can be responsible for this disorder. Although several traditional treatment methods involve medication and other counselling techniques, they also come with different side effects. Hence, the choice is now shifting to alternative treatment techniques. Herbal treatments are considered one of the most popular complementary and alternative medicine (CAM) administered. However, issues related to the safety and efficacy of herbal remedies for the treatment of ADHD need to be investigated further. This study aims to find out the recent advancement in evidence-based use of herbal remedies for ADHD by a comprehensive and systematic review that depicts the results of the published works on herbal therapy for the disorder. The electronic databases and the references retrieved from the included studies present related randomized controlled trials (RCTs) and open-label studies. Seven RCTs involving children and adolescents diagnosed with ADHD met the inclusion criteria. There is a fair indication of the efficacy and safety of Melissa officinalis L., Bacopa monnieri (L.) Wettst., Matricaria chamomilla L., and Valeriana officinalis L. from the studies evaluated in this systematic review for the treatment of various symptoms of ADHD. Limited evidence was found for Ginkgo biloba L. and pine bark extract. However, various other preparations from other plants did not show significant efficacy. There is inadequate proof to strongly support and recommend the administration of herbal medicines for ADHD, but more research is needed in the relevant field to popularize the alternative treatment approach.
... After the washout period, all ADHD subjects were provided with the other supplement in the second period for 4 weeks. The dosage of PE capsules was modified from the previous literature [10][11][12]. ADHD participants were provided 2 capsules (body weight more than 40 kg and less than 60 kg) or 3 capsules (body weight more than 60 kg) of PE (each capsules contained 50 mg PE) per day. One capsule contained 50 mg PE (Oligopin®, DRT, Dax, France) including of 67%~75% OPCs, 4%~10% catechin, 4%~10% ferrulate glucoside, 3%~8% taxifoliol glucoside, 1%~5% ferulic acid etc. [7]. ...
... In a randomized, controlled trial with sixty-one children suffering from ADHD, the efficacy of pycnogenol was tested by administering 1 mg/kg/day for a 1-month period of treatment. Compared to the placebo, pycnogenol treatment significantly improved attention, visual-motor coordination and concentration and reduced hyperactivity (Trebatická et al. 2006). Unexpectedly, no positive effects were obtained with pycnogenol in adults suffering from ADHD after 3 weeks of treatment with a dose of 2.22 mg/kg/day. ...
Substances with modulatory capabilities on certain aspects of human cognition have been revered as nootropics from the dawn of time. The plant kingdom provides most of the currently available nootropics of natural origin. Here, in this systematic review, we aim to provide state-of-the-art information regarding proven and unproven effects of plant-derived nootropics (PDNs) on human cognition in conditions of health and disease. Six independent searches, one for each neurocognitive domain (NCD), were performed in parallel using three independent scientific library databases: PubMed, Cochrane and Scopus. Only scientific studies and systematic reviews with humans published between January 2000 and November 2021 were reviewed, and 256 papers were included. Ginkgo biloba was the most relevant nootropic regarding perceptual and motor functions. Bacopa monnieri improves language, learning and memory. Withania somnifera (Ashwagandha) modulates anxiety and social-related cognitions. Caffeine enhances attention and executive functions. Together, the results from the compiled studies highlight the nootropic effects and the inconsistencies regarding PDNs that require further research.
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Background Previous research found that diets high in fruits and vegetables improved symptoms of attention deficit hyperactivity disorder (ADHD). Nevertheless, the relation between dietary polyphenol intake and the risk of ADHD was not assessed. Objective The purpose of this study was to see if there was a relationship between dietary polyphenol intake and the risk of ADHD in children in preschool and elementary school. Methods A total of 400 children aged 4 to 12 years old participated in this case-control research (200 children with diagnosed ADHD and 200 healthy controls). The presence of ADHD was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders-V criteria. To calculate dietary polyphenol intake, a 168-item food frequency questionnaire and the Phenol-Explorer database were used. Results The risk of incident ADHD for each unit increase of dietary polyphenol intake in the crude model showed an indirect association between dietary polyphenol intake and risk of ADHD (OR: 0.995, 95% CI = 0.994 to 0.996, P < 0.001). This finding was still significant even after adjusting for body mass index, energy intake, socioeconomic status, gender, and age (OR: 0.992, 95% CI = 0.989 to 0.995, P < 0.001). Conclusion We found that the increased dietary intake of polyphenols is associated with a lower risk of ADHD in preschool and school children. Prospective studies are needed to corroborate these observations.
The treatment of attention-deficit/hyperactivity disorder can be a very rewarding and challenging task. The management of this condition has impact on a child's performance in school in both academics and extracurriculars, and therefore, can be a determinant of what they are able to achieve and become. Treatment can also impact the child's self-image and ability to successfully interact with their peers. Adequate control of the disorder can break down barriers to successful development of a child's potential and ability to play a role in the work force someday.
Neurodegenerative diseases (NDs) represent one of the most important public health problems, and worldwide, hundreds of millions of people are affected by NDs, displaying strong evidence to these diseases is one of the most significant challenges to public health. Neurological disorders include several common diseases of the central and peripheral nervous system such as Alzheimer's disease and other dementia, epilepsy, headache disorders, multiple sclerosis, Parkinson's disease, and others. The discovery of substances capable of preventing or treating neurological disorders has been the goal of researchers for several years. New therapies and new molecules should be explored. In this context, natural compounds represent an important source for the development of new drugs. For example, between 1981 and 2014, from a total of 12 new approved molecules for the treatment of Parkinson's disease, only one was a synthetic drug, being the others biological, derived or inspired in a natural product. In the same line, > 50% of all new antidepressant molecules were synthetic/mimetic of a natural product. Anticholinesterases like physostigmine and neostigmine, opioids alkaloids, galantamine, are some examples of drugs utilized from derived plants for the treatment of neurological disorders, highlighting the relevance of studying and searching for new natural products for the treatment of neurological disorders. This chapter aimed to summarize the most important compounds originated from natural sources that were targets of clinical studies, associated with neurological and psychiatric disorders, obtaining a total of 13 articles, in the last 10 years. Also, we characterized these compounds structurally. Considering the vast diversity of plants, few herbal medicines or botanical drugs were approved for human use, in the last centuries, only few innovative therapeutic products have been developed, especially in the field of neurological diseases.
Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed mental disorder in children and a small proportion retain the disorder into adulthood. The primary feature of ADHD is inattentiveness that contributes to restlessness, and it is considered a neurodevelopmental disorder characterized by a 2- to 3-year delay in cortical maturation in children. Neurophysiological studies identify functional connectivity changes in the dorsolateral prefrontal cortex, insula, and anterior cingulate cortex. The sympathomimetics that act as dopamine agonists are the mainstay in pharmacological treatment. The current article addresses the definition and manifestations of attention-deficit disorder, comorbidities in children and adults, epidemiology, neurophysiology, and pharmacological treatment strategies. [Journal of Psychosocial Nursing and Mental Health Services, 58(5), 7-14.].
Pycnogenol (procyanidins extracted from the bark of French maritime pine, Pinus maritima Aiton) has been shown to be a potent free radical scavenger and an antioxidant phytochemical. The effects of pycnogenol on learning impairment and memory deficit in senescence-accelerated mouse (SAM) as a murine model of accelerated aging were determined. SAMP8, a strain of senescence-prone mice, exhibits immunodeficiency, hemopoietic dysfunction, learning impairment, and memory deficit. The effects of pycnogenol on learning performance and memory deficit were measured using step-through and step-down passive avoidance tests and shuttle box conditioned avoidance test. Oral feeding with pycnogenol for 2 months increased the retention rate in the step-through and the step-down tests and the rate of conditioned avoidance response in the shuttle box test. The latency of mice in the step-through test and the number of successful mice in the step-down test also increased with pycnogenol feeding. These results suggest that pycnogenol can improve learning impairment and memory deficit associated with aging.
Harald H. H. W. Schmidt and Ulrich Walter Medizinische Universitatsklinik Wiirzburg Klinische Biochemie und Pathobiochemie Versbacher Strasse 5 D-97078 Wiirzburg Federal Republic of Germany Nitroglycerine has been used for over a century to treat coronary heart disease, and it has long been suggested that humans synthesize oxides of nitrogen (Mitchell et al., 1916). These observations have recently been brought into focus by the demonstration that endogenous nitric oxide (NO) regulates mammalian blood vessels and other systems (Moncada and Higgs, 1991) such that virtually every mammalian cell is under the influence of NO. The three “classics” of NO-mediated functions-endothelium- dependent relaxation (Furchgott and Zawadzki, 1980) neurotransmission (Garthwaite et al., 1988; Gillespie et al., 1989) and cell-mediated immune response (Nathan and Hibbs, 1991)-have suggested principles for the mode of action of NO and for its functions. General Principles Networks In many systems, NO derives from two or more different cellular sources, forming networks of paracrine communi- cation (Figure 1). For example, we now know that vascular and bronchial NO originates not only from endothelial cells, where it iscalledendotheliumderived relaxing factor (EDRF), but also from adventitial nerves and epithelial cells (Schmidt et al., 1992a; Wilcox et al., 1992), where it mediates endothelium-independent smooth muscle relax- ation. Neurons use NO to regulate transmitter release of adjacent neurons (Meffert et al., 1994) and also to match cerebral blood flow with neuronal activity; similarly, bron- chial epithelial and endothelial cells use NO to match venti- lation and perfusion (Gaston et al., 1994). Macula densa renal tubular epithelial cells release NO to dilate the neigh- boring afferent artery and increase glomerular filtration (Wilcox et al., 1992). NO Toxicity NO is a double-edged sword (Table l), beneficial as a messenger or modulator and for immunologic self-defense, but potentially toxic. In several different scenarios (Figure 2) with factors such as oxidative stress, generation of reactive oxygen intermediates (ROls), and deficient anti- oxidant systems, NO switches from friend to foe. A pre- dominant mechanism by which this occurs is through the diffusion-limited reaction of NO with superoxide to gener- ate peroxynitrite (Beckman et al., 1990) which may modu- late signaling functions of NO (Gaston et al., 1994; Moro et al., 1994) and is directly cytotoxic (Beckman, 1991). e.g., by causing extensive protein tyrosine nitration (Beck- man et al., 1994).
Recent years have seen tremendous advances in understanding and treating Attention-Deficit/Hyperactivity Disorder (ADHD). Now in a revised and expanded third edition, this authoritative handbook brings the field up to date with current, practical information on nearly every aspect of the disorder. Drawing on his own and others' ongoing, influential research - and the wisdom gleaned from decades of front-line clinical experience - Russell A. Barkley provides insights and tools for professionals working with children, adolescents, or adults. Part I presents foundational knowledge about the nature and developmental course of ADHD and its neurological, genetic, and environmental underpinnings. The symptoms and subtypes of the disorder are discussed, as are associated cognitive and developmental challenges and psychiatric comorbidities. In Parts II and III, Barkley is joined by other leading experts who offer state-of-the-art guidelines for clinical management. Assessment instruments and procedures are described in detail, with expanded coverage of adult assessment. Treatment chapters then review the full array of available approaches - parent training programs, family-focused intervention for teens, school- and classroom-based approaches, psychological counseling, and pharmacotherapy - integrating findings from hundreds of new studies. The volume also addresses such developments as once-daily sustained delivery systems for stimulant medications and a new medication, atomoxetine. Of special note, a new chapter has been added on combined therapies. Chapters in the third edition now conclude with user-friendly Key Clinical Points. This comprehensive volume is intended for a broad range of professionals, including child and adult clinical psychologists and psychiatrists, school psychologists, and pediatricians. It serves as a scholarly yet accessible text for graduate-level courses. Note: Practitioners wishing to implement the assessment and treatment recommendations in the Handbook are advised to purchase the companion Workbook, which contains a complete set of forms, questionnaires, and handouts, in a large-size format with permission to photocopy. (PsycINFO Database Record (c) 2012 APA, all rights reserved)(jacket)
1. We investigated the effects of NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthase, on the performance of rats in a radial arm maze and in habituation tasks, and on monoamine metabolism in the brain. 2. Daily administration of L-NAME (10-60 mg kg-1) resulted in a dose-dependent impairment of performance during the acquisition of the radial arm maze task, while it failed to affect performance in those rats that had previously acquired the task. 3. The rate of decrease in locomotor activity in the habituation task in the L-NAME-treated rats was significantly less than that in control rats. 4. NG-nitro-D-arginine methyl ester (D-NAME, a less active inhibitor of NO synthase) showed no effects in the above behavioural tasks. 5. NO synthase activity was significantly decreased in both the L-NAME and D-NAME-treated rats, with the magnitude of inhibition being greater in the L-NAME-treated animals. 6. The content of 5-hydroxyindoleacetic acid (5-HIAA) in the hippocampus and the 5-HIAA/5-hydroxytryptamine ratio in the hippocampus and cortex were significantly decreased in the L-NAME (60 mg kg-1)-treated rats compared with these values in the controls. 7. Striatal 3,4-dihydroxyphenylacetic acid (DOPAC) content was significantly increased in the L-NAME (60 mg kg-1)-treated rats compared with the values in the controls, while the DOPAC/dopamine ratio was not changed. 8. These results suggest that: (i) NO may play an important role in performance during the acquisition,but not retention, of the radial arm maze task, and (ii) that endogenous NO may be involved in the regulation of monoamine metabolism.