Received: 14 May 2020 Revised: 6 November 2020 Accepted: 14 January 2021

DOI: 10.1002/ptr.7036

RESEARCH ARTICLE

Complementary effects of pine bark extract supplementation

on inattention, impulsivity, and antioxidative status in children
with attention-deficit hyperactivity disorder: A double-blinded
randomized placebo-controlled cross-over study

Cheng-Dien Hsu1 | Li-Hsuan Hsieh2 | Ya-Ling Chen2 | I-Cheng Lin3 |

Ying-Ru Chen3 | Chih-Chi Chen3 | Hitoshi Shirakawa4 | Suh-Ching Yang2,5,6

1
Department of Psychiatry, Taiwan Adventist
Hospital, Taipei, Taiwan The purpose of this study was to investigate the complementary effects of polyphe-
2
School of Nutrition and Health Sciences, nolic compounds from pine bark extract (PE) as a strong antioxidative substrate on
Taipei Medical University, Taipei, Taiwan
3
the symptoms of inattention and impulsivity in children with attention-deficit
Department of Psychiatry, Shuang Ho
Hospital, New Taipei City, Taiwan hyperactivity disorder (ADHD). This was a randomized, double-blind, crossover,
4
Laboratory of Nutrition, Graduate School of placebo-controlled study that included two experimental units (4 weeks with PE sup-
Agricultural Science, Tohoku University,
Sendai, Japan
plementation and 4 weeks with placebo supplementation) separated by a 2-week
5
Research Center of Geriatric Nutrition, washout period. ADHD participants were supplemented with 25 mg or 50 mg
College of Nutrition, Taipei Medical University, PE. We recruited 20 participants (17 boys and 3 girls) with a mean age of 10.0
Taipei, Taiwan
6 ± 2.1 years. PE supplementation caused a significant reduction in the inattention and
Nutrition Research Center, Taipei Medical
University Hospital, Taipei, Taiwan hyperactivity-impulsivity items of SNAP-IV. During the period of PE supplementa-
tion, the item of commissions in the Continuous Performance Test III (CPT III) signifi-
Correspondence
Suh-Ching Yang, School of Nutrition and cantly decreased, which was used to evaluate the symptoms of inattention and
Health Sciences, Taipei Medical University,
impulsivity. In addition, the erythrocytic reduced glutathione/oxidized glutathione
Taipei 11031, Taiwan.
Email: sokei@tmu.edu.tw ratio significantly increased, and the plasma TBARs level significantly decreased after
4 weeks of PE supplementation. However, there was no significant correlation
between CPT III (commission) and antioxidative status indictors. PE supplementation
may have potential effects of ameliorating inattention and impulsivity, and elevating
the antioxidative status in children with ADHD.

KEYWORDS
attention-deficit hyperactivity disorder, oxidative stress, pine bark extract

1 | I N T RO DU CT I O N National Health Insurance database and found that the prevalence of

Attention-deficit hyperactivity disorder (ADHD) is one of the most
prevalent neurobiological disorders in the world and presents a com-
plex, highly inheritable etiology (Polanczyk, Willcutt, Salum, Kieling, &
Rohde, 2014). The global prevalence of ADHD in school-age children
is 5.3%–7.1%, which varies according to different diagnostic tools,
diagnostic criteria, and case samples (Thomas, Sanders, Doust,
Beller, & Glasziou, 2015). On the other hand, Huang et al. used a
ADHD among Taiwanese school children was 7%–12% and was more
common among boys (14.9%) than girls (4.5%) (Huang, Chu, Cheng, &
Weng, 2014). This difference is partially because boys have explicit
behaviors, which are more easily exhibited in early stages. Conversely,
girls often show inattention, anxiety, and depression. It was reported
that in around 60% of children with ADHD, the problems of inatten-
tion and hyperactivity continue to occur in adulthood (Barkley,
Fischer, Smallish, & Fletcher, 2002).

Phytotherapy Research. 2021;1–10. wileyonlinelibrary.com/journal/ptr © 2021 John Wiley & Sons, Ltd. 1
2 HSU ET AL.
According to the World Health Organization (WHO)'s interna-
tional classification of disease-10 (ICD-10) and the Diagnostic Statisti-
cal Manual of Mental Disorders, fourth edition (DSM-IV), there are
three types of ADHD: combined presentation, predominant hyperac-
tivity/impulsivity, and predominant inattention (Faraone, Biederman, &
Mick, 2006). Long-term multimodal treatment, including medication
and behavioral therapy, is ideally used to control symptoms of ADHD;
however, up to 25% of ADHD children do not respond very well to
drugs or have adverse reactions such as nausea, insomnia, or weight
loss (Storebo et al., 2015). Therefore, developing complementary ther-
apy is an important issue in current ADHD-related research including
herbal medicines and nutritional supplements.
Pine bark is obtained from the pine tree (Pinus pinaster), harvested
from the largest cultivated forest in Europe (Segal, Penman, &
Piriou, 2018). Major constituents of pine bark extract (PE) are polyphe-
nols, such as oligomeric procyanidins (OPCs) of catechin, epicatechin,
and taxifolin (Segal et al., 2018). PE has the strong antioxidative capac-
ity and widely used in many diseases, including asthma, cardiovascular
diseases, metabolic syndrome, and so forth (Belcaro et al., 2013;
Enseleit et al., 2012). It was also indicated that PE supplementation
may provide a promising approach for the treatment of oxidative
stress-related neurodegeneration in conditions such as Parkinson's dis-
ease and Alzheimer's disease in rat model (Ishrat et al., 2009). It was
surmised that PE was directly or indirectly related to the cell membrane
permeability and regulates the transport of catecholamines by means
of decreasing oxidative stress in brain cells (Lopresti et al., 2015;
Trebaticka & Ďuračková, 2015). Although the brain has a large potential
oxidative capacity which consumes about 20% of the oxygen available
through respiration, but a limited ability to resist oxidative stress. More-
over, brain has a low activity of antioxidative enzymes, such as catalase,
glutathione peroxidase, and superoxide dismutase. These facts may
cause the high sensitive property to oxidative and peroxidative dam-
ages to biomolecules in the brain (Lopresti et al., 2015). It has been
reported that malondialdehyde (MDA), the marker of lipoperoxidation,
was found increased in 20 adult patients and correlated with the score
of hyperactivity (Bulut et al., 2007). Other research found that 61 chil-
dren with ADHD showed the increased oxidative damage to DNA rep-
resented by 8-oxo-7,8-dihydroxyquanine and decreased total
antioxidant status (TAS) in comparison to the controls (Chovanová
et al., 2006). That is to say, ADHD symptoms were related with oxida-
tive stress in ADHD patients.
Therefore, we hypothesized that PE could improve symptoms of
inattention and impulsivity which are well correlated with elevated
antioxidative status in patients with ADHD. This study was carried
out to verify this hypothesis.
2 | MATERIALS AND METHODS
2.1 | Participant recruitment
The study was approved by the Taipei Medical University (TMU)-
Joint Institutional Review Board (protocol ID: N201706026,
ClinicalTrails.gov ID: NCT03368690). All procedures were con-
ducted according to principles expressed in the Declaration of Hel-
sinki. Written informed consent was obtained from participants'
parents.
Recruitment was conducted in the psychiatric department of Tai-
wan Adventist Hospital, Hsuang Ho Hospital, and TMU Hospital from
August 2017 to June 2019. Participants, who were aged 7–20 years
and attended a preliminary screening session using the Swanson,
Nolan, and Pelham-IV (SNAP-IV) questionnaire, which was filled in by
their parents and teachers. Subjects who were in the >85 percentile
of SNAP-IV were invited to receive further evaluation. The Child
Behavior Checklist (CBCL) was used to evaluate whether participants
had other emotional or behavioral problems or not. Finally, partici-
pants were recruited into the study after being diagnosed with ADHD
by a psychiatrist using Diagnostic and Statistical Manual of Mental
Disorders, fourth Edition, Text Revision (DSM-IV-TR). Moreover, par-
ticipants with ADHD were also excluded if they were taking any
ADHD medications, blood pressure medications, or dietary supple-
ments, or if they had neurological disorders such as epilepsy and intel-
lectual disabilities. Mental disorders (autism, psychosis, bipolar
disorder, major depressive disorder, anxiety, personality disorder, con-
duct disorder, tic disorder etc.) and chronic diseases (liver, kidney, gas-
trointestinal, cardiovascular diseases, etc.) were also listed as
exclusion criteria.
2.2 | Intervention
This was a randomized, double-blind, placebo-controlled crossover
study. The randomization was performed by drawing lots. Neither the
participants nor researchers knew which person was in which group.
There were two experimental units including placebo and PE supple-
mentation. The washout period was 2 weeks. In the first experimental
unit (in weeks 1–4), ADHD subjects were randomly provided with pla-
cebo or PE supplementation for 4 weeks. After the washout period
(in weeks 5 and 6), all ADHD subjects were provided with the other
supplement in the second experimental unit for 4 weeks (in weeks
7–10). The dosage of PE capsules was modified from the previous lit-
erature (Chovanová et al., 2006; Dvořáková et al., 2007; Trebatická
et al., 2006). ADHD subjects were provided one capsule (with a body
weight [BW] of ≤50 kg) or two capsules (with a BW of >50 kg) of PE
per day which one capsule contained 25 mg PE (Oligopin®, DRT, Dax,
France) including of 67%–75% OPCs, 4%–10% catechin, 4%–10% fer-
rulate glucoside, 3%–8% taxifoliol glucoside, 1%–5% ferulic acid, and
so forth (Segal et al., 2018). Placebo supplements contained maltodex-
trin (75%) and magnesium stearate (25%).
2.3 | Psychological examination
A psychological examination was carried out at the baseline, and at
weeks 4, 7, and 10. The evaluation process was assisted by
psychiatrists.
HSU ET AL.
The SNAP-IV questionnaire includes 26 questions concerning
inattention (nos. 1–9), hyperactivity and impulsivity (nos. 10–18), and
oppositional defiant behavior (nos. 19–26). Each part was scored on a
four-point scoring method, where 0 means “no,” 1 means “a little bit,”
2 means “quite a lot,” and 3 means “very much” (Liu, 2006). The ques-
tionnaire was filled out by parents and teachers. The continuous per-
formance test (CPT) is used to evaluate the inattention, impulsivity,
sustained attention, and vigilance of healthy people and it can also be
used as part of diagnostic procedures in ADHD patients. Conners'
CPT-III was used in this study to evaluate ADHD symptoms. It is a
14-min computerized assessment tool, which involves rapid presenta-
tion of visual stimuli. During the test, respondents are required to
respond when any letter appears, except the non-target letter “X”
(Conners & Staff, 2015).
2.4 | Blood collection and analysis
The blood of participants was collected after 8 h of fasting at the
baseline, and at weeks 4 and 10 in TMU Hospital. Ten milliliters of
blood were separated into three tubes without and with anticoagulant
including K2EDTA and lithium heparin for the following
measurements.
The ratio of erythrocytic reduced form of glutathione (GSH) to the
disulfide form (GSSG) was measured as an indicator of antioxidative
capacity according to the previous study (Griffith, 1980). The lipid per-
oxidation biomarkers were represented by plasma levels of
2-thiobarbituric acid-reactive substance (TBARS) and 8-isoprostane
which were measured by commercial enzyme-linked immunosorbent
assay (ELISA) kits (TBARS: no. 10009055, Cayman Chemical, Ann Arbor,
MI; 8-isoprostane: no. 516351, Cayman Chemical, Ann Arbor, MI).
In order to monitor the safety of supplements, biochemical param-
eters were determined during the experimental period including blood
cell analysis, liver function indicators (aspartate transaminase and ala-
nine transaminase activities), blood lipid profiles, nutritional status
indicator (albumin level), renal function indicator (uric acid level), and
iron nutrition status (ferritin level, iron level, and total iron-binding
capacity). All items were evaluated with an automated clinical chemis-
try analyzer (SYNCHRON CX System 7,170, Hitachi, Tokyo, Japan).
2.5 | Dietary intake assessment
Food diaries were completed during weeks 2, 4, 6, and 10, including a
3-day dietary record and a food-frequency questionnaire, which were
validated in our previous study (J.-R. Chen, Hsu, Hsu, Hwang, &
Yang, 2004). All data were analyzed by Nutrients Analysis Software
(2018) established by the Taiwan Dietitian Association.
The 3-day dietary record included two weekdays and one week-
end day. Participants were instructed by the researchers before the
study. Food frequency was assessed by a dietician in weeks 4, 7, and
10. In total, 27 items were classified into six categories of food (staple
foods, vegetables, fruits, total protein food, milk, sweets, and sugar
3
drinks) as a semiquantitative food-frequency questionnaire. Four
levels of eating frequency included 0–1 (never and less 1 time/week),
1–4 (included 1 and less than 4) times/week, 4–7 (included 4 and less
than 7) times/week, and more than 7 (included 7) times/week.
2.6 | Statistical analysis
Statistical analyses were performed with SAS version 9.4 (SAS Insti-
tute, Cary, NC), and all values are expressed as the mean ± standard
deviation (SD). The normality of population was verified with
Shapiro–Wilk test and verified the data was not normally distributed.
Thus, differences among groups were compared by the Wilcoxon
sign-rank test for matched or dependent samples. In addition, Spe-
arman's correlation analysis was used to investigate correlations
between CPTIII and antioxidative indicators. Chi-square test (categori-
cal variables) was used to evaluate whether food frequency was
affected by the type of supplements. p value less than .05 was consid-
ered statistically significant.
3 | RE SU LT S
3.1 | General characteristics, growth development,
and physiological status
Twenty ADHD subjects, including 17 males and 3 females, completed
all the evaluation in this study (Figure 1), and their general characteris-
tics are shown in Table 1. The mean age at baseline was 10.0
± 2.1 years. All participants were within the normal range of Taiwanese
growth curves (W. Chen & Chang, 2010). Blood pressure values were
also within normal ranges under 120/80 mmHg. After 10 weeks, the
heights and BWs had significantly increased compared to the baseline.
As shown in Table 1, ADHD participants maintained their growth
and physiological status during the experiment period. In addition, partic-
ipants did not report any adverse events such as nausea, vomiting, poor
appetite, and so forth. The 50% lethal dose (LD50) of PE was >2,000 mg/
kg BW, and the no-observed-adverse effect level (NOAEL) was
1,000 mg/kg BW, as derived from a 90-day study of male and female
rats (Segal et al., 2018). Previous studies also found that ADHD patients
who received 1 mg/kg BW/day of PE showed no side effects during a
4-week experimental period (Y.-R. Chen, Su, Piriou, & Yang, 2017;
Chovanová et al., 2006). Only one ADHD patient was reported to have
had moderate gastric discomfort after PE supplementation in the previ-
ous study (1 mg/kg BW/day) (Chovanová et al., 2006).
3.2 | Effect of PE supplementation on the
psychological examination
Results of the SNAP-IV questionnaire after 4 weeks of supplementa-
tion with PE or a placebo are shown in Table 2. Supplementation with
both of placebo and PE caused a significant (p < .05) reduction in the
4 HSU ET AL.

F I G U R E 1 CONSORT flow diagram for attention-deficit hyperactive disorder participants treating with polyphenolic compounds from pine
bark extract or placebo. Forty-seven participants attended a preliminary screening session using the Swanson, Nolan, and Pelham-IV (SNAP-IV)
questionnaire, which was filled in by their parents and teachers. Subjects who were in the >85 percentile of SNAP-IV were invited to receive
further evaluation. The CBCL was used to evaluate whether or not participants had other emotional or behavioral problems. Finally, participants
were recruited into the study after being diagnosed with ADHD by a psychiatrist using Diagnostic and Statistical Manual of Mental Disorders,
fourth Edition, Text Revision (DSM-IV-TR). Fifteen participants were excluded because they did not pass the preliminary screening, such as lower
SNAP-IV (less than 85 percentile), other emotional or behavioral problems (depression, oppositional defiant) or lower intelligence quotient. Two
participants were excluded after PE supplementation for 4 weeks because they could not follow the time schedule. Placebo, 4-week
supplementation with maltodextrin and magnesium stearate; PE, 4-week supplementation of polyphenolic compounds from pine bark extract

T A B L E 1 Effects of polyphenolic compounds from pine bark extract on the anthropometric assessment in attention-deficit hyperactive
disorder participants

p value

Baseline Placebo PE Baseline × placebo Baseline × PE Placebo × PE

Sex (male/female) 17/3 17/3 17/3
Age (years) 10.0 ± 2.1 10.1 ± 2.1* 10.1 ± 2.1* <.001 <.001 .666
Height (cm) 140.4 ± 9.7 141.7 ± 9.6* 141.6 ± 10.0* <.001 <.001 .796
Body weight (kg) 35.9 ± 11.2 36.4 ± 11.0* 36.4 ± 10.9* .010 .023 .912
Fat mass (%) 20.3 ± 8 19.2 ± 7.3 20.4 ± 7.9† .945 .089 .038
2
BMI (kg/m ) 18.1 ± 4.3 18.5 ± 4.4 18.3 ± 4.1 .345 .503 .461
SBP (mm Hg) 102.2 ± 12.3 100.1 ± ± 13.9 98.3 ± 13.7 .417 .160 .395
DBP (mm Hg) 64.8 ± 10.3 61.1 ± 11.5 61.8 ± 10.8 .087 .123 .754

Note: Values are expressed as the mean ± SD.

Abbreviations: Baseline, before supplementation; Placebo, 4-week supplementation with maltodextrin and magnesium stearate; PE, 4-week
supplementation of polyphenolic compounds from pine bark extract. BMI, body-mass index; DBP, diastolic blood pressure; SBP, systolic blood pressure.
*Significant difference compared to baseline (p < .05). †Significant difference compared to placebo (p < .05).

inattention item of the parent SNAP-IV compared to the baseline. The
inattention item of the teacher SNAP-IV was significantly (p < .05)
lower after the placebo and PE supplementation period compared to
the baseline. Additionally, PE supplementation exhibited a significantly
(p < .05) lower rating than placebo supplementation did. In the
hyperactivity-impulsivity item of the teacher, ADHD participants
showed a significantly (p < .05) lower rating in the PE supplementa-
tion period.
After 4 weeks of supplementation with PE and the placebo, results
of CPT-III are shown in Table 3. The T-score of commissions as indica-
tors of inattention and impulsivity was significantly (p = .048) reduced
during the PE supplementation period compared to the baseline.
HSU ET AL. 5

T A B L E 2 Effects of polyphenolic compounds from pine bark extract on the SNAP-IV questionnaire in attention-deficit hyperactive disorder
participants

Percentile rank p value

Baseline Placebo PE Baseline × placebo Baseline × PE Placebo × PE

Parent
Inattention 92.9 ± 7.1 83.2 ± 14.1* 86.8 ± 11.2* .007 .023 .194
Hyperactivity-impulsivity 87.3 ± 16.6 79.3 ± 22.3 79.2 ± 23.9 .072 .108 .968
Teacher
Inattention 91.4 ± 6.8 83.5 ± 9.6* 73.4 ± 22.2*,† .003 .002 .024
,†
Hyperactivity-impulsivity 84.3 ± 15.8 84.8 ± 16.9 77.3 ± 18.4* .802 .029 .024

Note: Values are expressed as the mean ± SD.

Abbreviations: Baseline, before supplementation; Placebo, 4-week supplementation with maltodextrin and magnesium stearate; PE, 4-week
supplementation of polyphenolic compounds from pine bark extract.
*Significant difference compared to baseline (p < .05). †Significant difference compared to placebo (p < .05).

TABLE 3 Effects of polyphenolic compounds from pine bark extract on CPT-III in attention-deficit hyperactive disorder participants

T-score p value

Baseline Placebo PE Baseline × placebo Baseline × PE Placebo × PE

Inattention
Detectability 50.9 ±11.4 52.5 ± 8.7 50.4 ± 9.98 .301 .791 .144
Omissions 52.4 ±10.7 55.9 ± 15.5 55.9 ± 17.69 .147 .180 .986
Commissions 48.6 ± 11.3 47.5 ± 9.1 45.4 ± 9.53* .556 .048 .271
HRT 59.4 ± 10.9 62.7 ± 14.4 63.0 ± 11.88 .212 .090 .797
HRT-SD 59.8 ± 13.6 64.3 ± 13.1 62.8 ± 11.03 .090 .165 .442
Variability 53.9 ± 12.9 53.0 ± 16.0 51.6 ± 14.41 .819 .625 .787
Impulsivity
HRT 59.4 ± 10.9 62.7 ± 14.4 63.0 ± 11.88 .212 .090 .797
Commissions 48.6 ± 11.3 47.5 ± 9.1 45.4 ± 9.53* .556 .048 .271
Perseverations 56.3 ± 12.5 55.7 ± 11.1 58.1 ± 11.57 .822 .468 .299
Sustained attention
HRT-BC 53.1 ± 12.4 49.7 ± 15.2 51.8 ± 11.73 .322 .720 .648
Vigilance
HRT-ISI-C 62.6 ± 12.5 64.7 ± 11.7 67.2 ± 10.97 .525 .242 .335

Note: Values are expressed as the mean ± SD.

Abbreviations: Baseline, before supplementation; Placebo, 4-week supplementation with maltodextrin and magnesium stearate; PE, 4-week
supplementation with polyphenolic compounds from pine bark extract; CPT-III, continuous performance test III; HRT, hit reaction time; HRT-BC, hit
reaction time-block change; HRT-ISI-C, hit reaction time-inter-stimulus interval-change; HRT-SD, hit reaction time-standard deviation.
*Significant difference compared to baseline (p < .05).

3.3 | Effect of PE supplementation on the correlation was not observed between CPT-III (commissions) and the
antioxidative status antioxidative status.

After 4 weeks of PE supplementation, the erythrocytic GSH/GSSG

ratio was significantly (p < .05) higher compared to the baseline and
placebo supplementation (Table 4). In addition, compared to placebo
supplementation, the plasma TBARS level was significantly (p < .05)
lower after PE supplementation (Table 4). However, there was no sig-
nificant difference in plasma 8-isoprostane levels among the baseline,
placebo, and PE supplementation. Furthermore, a significant
3.4 | Effect of PE supplementation on biochemical
parameters
Changes in biochemical parameters of ADHD participants during the
experimental period are shown in Table 5. During the placebo supple-
mentation period, the ALT activity and potassium level were
6 HSU ET AL.
T A B L E 4 Effects of polyphenolic compounds from pine bark extract on the ratio of erythrocytic reduced glutathione/oxidized glutathione in
attention-deficit hyperactive disorder participants
Baseline Placebo
Erythrocytic GSH/GSSG ratio 3.3 ± 1.9 3.4 ± 1.6
Plasma TBARS (μM) 6.4 ± 5.0 7.6 ± 5.1
Plasma 8-isoprostane (pg/ml) 89.3 ± 74.9 90.5 ± 78.0
Note: Values are expressed as the mean ± SD.
Abbreviations: Baseline, before supplementation; Placebo, 4-week supplementation with maltodextrin and magnesium stearate; PE, 4-week
supplementation with polyphenolic compounds from pine bark extract; GSH, reduced glutathione; GSSG, oxidized glutathione; TBARS, 2-thiobarbituric
acid-reactive substance.
*Significant difference compared to baseline (p < .05). †Significant difference compared to placebo (p < .05).
significantly (p < .05) higher compared to the baseline. On the other
hand, during the PE supplementation period, AST activity, ALT activ-
ity, and BUN level were also significantly higher, whereas the sodium
level was significantly lower compared to the baseline, but the values
were all still within normal ranges.
3.5 | Effect of PE supplementation on dietary
intake
Dietary intake and food frequency during the experimental period are
shown in the Data S1 and S2. There was no difference between the
placebo and PE supplementation periods.
4 | DISCUSSION
4.1 | Neuropsychological function
SNAP-IV is a well-known parent-based questionnaire, which is fre-
quently used as a primary outcome measure in intervention studies
(Filho et al., 2005; Nobel, Brunnekreef, Schachar, van den
Hoofdakker, & Hoekstra, 2019). In this study, it indicated that the
inattention rating of ADHD participants significantly improved based
on the parent and teacher SNAP-IV after PE supplementation
(Table 2). In particular, hyperactivity-impulsivity rating by teachers
also significantly improved during the PE supplementation period
(Table 2). It was pointed out by Chou et al. that teacher ratings are
closely related to ADHD symptoms, because classroom behavior is
usually more strictly controlled than that at home (Chou, Chen, Wu,
Chang, & Huang, 2017). However, supplementation with placebo also
showed the improvement of inattention based on SNAP-IV when
compared with baseline. The reason was not clear, thus we used the
other assessment tool, such as CPT-III, to confirm the data obtained
from questionnaires.
Although SNAP-IV is a useful screening tool and has had good
concordance with clinical impressions of pediatricians in terms of the
presence/absence of ADHD based on DSM-IV criteria, the CPT-III is
also used to evaluate inattention and impulsivity in ADHD
p value
PE Baseline × placebo Baseline × PE Placebo × PE
4.6 ± 2.0*,† .9354 .0358 .0336
5.2 ± 3.7† .0906 .1067 .0026
80.3 ± 75.0 .8354 .1486 .1954
participants in order to quantitatively analyze data (Alda & Serrano-
Troncoso, 2013). There are two indicators in CPT-III for evaluating
inattention and impulsivity, including both of omission and commis-
sion for inattention, commission for impulsivity. Omission is when a
respondent shows no response when the target alphabet appears on
the computer screen, whereas commission suggests that the respon-
dent gives an incorrect response to non-targets. A high commission
rating combined with a fast hit-reaction time (HRT) may indicate
either inattentiveness or impulsivity (Hall et al., 2016). In this study,
improvement in inattention and impulsivity of ADHD participants was
observed during the PE supplementation period based on a reduction
in commissions (Table 3). Trebaticka et al. indicated that 6–14-year-
old children with ADHD showed significant improvement in inatten-
tion and hyperactivity after supplementation with PE (1 mg/kg
BW/day) for 4 weeks using the child attention problem (CAP) teacher
rating scale as an evaluation tool (Trebaticka & Ďuračková, 2015).
Even though the evaluation tool of ADHD symptoms differed among
these related studies, the potential of PE to ameliorate ADHD symp-
toms was expected. In this study, an administered questionnaire
(SNAP-IV) and quantitative data (CPT-III) were used to evaluate
improvements in ADHD symptoms. Based on a reduction in the
SNAP-IV rating and commission score during the PE supplementation
period, we speculated that the symptoms of inattention and impulsiv-
ity were improved after 4 weeks of PE supplementation in ADHD
participants.
4.2 | Antioxidative status
As shown in Table 4, the erythrocytic GSH/GSSG ratio significantly
increased, whereas the plasma TBARS level significantly decreased
during the PE supplementation period. Dvorakova et al. also reported
that the erythrocytic GSH/GSSG ratio was increased in children with
ADHD after PE supplementation (1 mg/kg BW/day) for 4 weeks
(Dvořáková et al., 2007). Thus, the antioxidative capacity can be con-
sidered to have been elevated in ADHD participants due to the abun-
dant antioxidants in PE such as OPCs. The acidic environment of the
human stomach does not readily degrade OPCs; therefore, absorption
rates in the upper gastrointestinal tract are not high. However,
HSU ET AL. 7

T A B L E 5 Effects of polyphenolic compounds from pine bark extract on biochemical parameters in attention-deficit hyperactive disorder
participants

p value

Baseline Placebo PE Baseline × placebo Baseline × PE Placebo × PE

Liver function
AST/SGOT (U/L) 24.5 ± 5.2 26.5 ± 3.9 26.8 ± 5.0* .064 .006 .722
ALT/SGPT (U/L) 16.0 ± 5.0 17.7 ± 5.3* 18.6 ± 4.7* .053 .018 .427
Total bilirubin (mg/dl) 0.5 ± 0.2 0.5 ± 0.2 0.5 ± 0.2 .494 .226 .530
Kidney function
BUN (mg/dl) 12.9 ± 3.7 14.0 ± 3.9 15.0 ± 3.7* .129 .020 .270
Creatinine (mg/dl) 0.6 ± 0.1 0.5 ± 0.1 0.5 ± 0.1 .114 .394 .361
Uric acid (mg/dl) 4.4 ± 1.0 4.6 ± 0.9 4.6 ± 0.9 .169 .183 .910
Sodium (meq/L) 139.8 ± 1.5 138.9 ± 2.6 138.2 ± 2.6* .168 .029 .395
Potassium (meq/L) 5.0 ± 0.6 5.2 ± 0.7* 5.3 ± 0.6* .067 .041 .877
Protein nutrition status
Protein, total (g/dl) 7.3 ± 0.5 7.3 ± 0.4 7.1 ± 1.0 .611 .379 .165
Albumin (g/dl) 4.5 ± 0.8 4.7 ± 0.2 4.6 ± 0.3 .322 .583 .213
Globulin (g/dl) 2.6 ± 0.3 2.7 ± 0.3 2.6 ± 0.3 .545 1.000 .554
Lipid profile
Triglyceride (mg/dl) 62.3 ± 30.1 58.9 ± 18.4 70.8 ± 43.2 .623 .399 .105
Cholesterol (mg/dl) 169.8 ± 30.2 167.1 ± 26.3 167.2 ± 28.8 .608 .637 .980
HDL-C (mg/dl) 66.5 ± 13.6 65.3 ± 12.8 64.9 ± 13.0 .397 .464 .836
LDL-C (mg/dl) 87.0 ± 20.8 88.5 ± 19.8 90.0 ± 20.6 .691 .451 .650
T-C/HDL (ratio) 2.6 ± 0.4 2.6 ± 0.5 2.6 ± 0.4 .886 .816 .938
Hematology
WBCs (103/μl) 6.8 ± 2.0 6.6 ± 1.7 6.6 ± 1.0 .739 .724 .982
RBCs (106/μl) 5.0 ± 0.6 5.1 ± 0.5 5.1 ± 0.6 .570 .789 .769
Hemoglobin (g/dl) 13.6 ± 0.8 13.7 ± 0.8 13.7 ± 0.9 .752 .697 .894
Hematocrit (%) 40.7 ± 2.6 41.1 ± 2.7 39.4 ± 6.9 .328 .430 .299
MCV (fL) 81.5 ± 6.0 81.6 ± 6.3 81.4 ± 5.8 .880 .869 .807
MCH (pg) 27.3 ± 2.4 27.5 ± 2.5 27.3 ± 2.4 .139 .614 .193
MCHC (g/dl) 33.5 ± 0.8 33.4 ± 1.0 33.6 ± 1.0 .609 .723 .240
Platelet (103/μl) 325.6 ± 82.1 319.3 ± 77.6 316.8 ± 66.2 .474 .256 .776
Neutrophil Seg. (%) 49.5 ± 10.1 49.6 ± 7.4 47.9 ± 6.9 .975 .603 .440
Lymphocyte (%) 41.0 ± 8.8 39.9 ± 6.7 41.2 ± 6.4 .676 .939 .513
Monocyte (%) 5.0 ± 1.4 5.4 ± 1.3 5.0 ± 1.0 .136 .939 .105
Eosinophil (%) 3.8 ± 3.1 4.5 ± 3.3 5.0 ± 3.3 .305 .108 .156
Basophil (%) 0.6 ± 0.2 0.7 ± 0.3 0.7 ± 0.3 .765 .595 .731
Iron status
Iron (μg/dl) 74.6 ± 35.1 79.3 ± 28.8 84.8 ± 29.7 .591 .241 .427
TIBC (μg/dl) 353.2 ± 39.95 359.7 ± 35.5 353.0 ± 38.3 .314 .983 .212
Ferritin (ng/ml) 55.3 ± 36.69 50.1 ± 36.9 48.3 ± 25.1 .567 .381 .762

Note: Values are expressed as the mean ± SD.

Abbreviations: Baseline, before supplementation; Placebo, 4-week supplementation with maltodextrin and magnesium stearate; PE, 4-week
supplementation with polyphenolic compounds from pine bark extract; ALT, alanine aminotransferase; ALT, aspartate aminotransferase; BUN, blood urea
nitrogen; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MCH, mean corpuscular hemoglobin; MCHC, mean
corpuscular hemoglobin concentration; MCV, mean corpuscular volume; RBCs, red blood cells; TC, total cholesterol; TIBC, total iron-binding capacity;
WBCs, white blood cells.
*Significant difference compared to baseline (p < .05).
8 HSU ET AL.
available research demonstrated that even low amount observed in
urine after an oral feeding were enough to increase the plasma antiox-
idant capacity (Duthie et al., 1998; Serafini, Maiani, & Ferro-
Luzzi, 1998; Whitehead, Robinson, Allaway, Syms, & Hale, 1995). On
the other hand, OPCs can be degraded by colon flora and produced
metabolites, which have antioxidant and protective effects in colon
tissue (Bokkenheuser, Shackleton, & Winter, 1987; Scalbert
et al., 2000). However, the determination of only one or two markers
of oxidative stress cannot reflect the real redox state in the organism.
Therefore, the evaluation of total oxidative status (TOS), TAS, and
total antioxidant capacity (TAC) and could be useful for identification
of redox imbalance in patients with ADHD.
However, there was no obvious change in plasma 8-isoprostane
levels among the three checkpoints in this study. 8-Isoprostane is a
prostaglandin-F2-like compound belonging to the F2 isoprostane class
that is produced in vivo by the free radical-catalyzed peroxidation of
arachidonic acid (Kaviarasan, Muniandy, Qvist, & Ismail, 2009). Many
studies have proven that 8-isoprostane is considered an ideal marker
for investigating the pathophysiology of oxidative injury such as dia-
betes, cardiovascular diseases, and asthma (Bauer et al., 2014). Some
reports mentioned that psychological diseases were also associated
with oxidative stress (Sharma, 2014), but blood 8-isoprostane levels
have only been discussed in Alzheimer's disease, Parkinson's disease,
and schizophrenia (Irizarry, Yao, Hyman, Growdon, & Pratico, 2007;
Pawełczyk, Grancow-Grabka, Trafalska, Szemraj, & Pawełczyk, 2017).
In addition, data on plasma 8-isoprostane levels showed a large stan-
dard deviation among ADHD participants in this study. Therefore, fur-
ther investigation related to plasma 8-isoprostane and ADHD is
necessary in the future.
4.3 | Correlations between neuropsychological
functions and the antioxidative status
In order to evaluate statistical relationships between ADHD symp-
toms and antioxidant status, the correlation between CPT-III and
antioxidative indicators was determined. A significant correlation was
not observed between results of the CPTIII (commissions) and
antioxidative status indicators in each period (r = −.16689, p = .508
for erythrocytic GSH/GSSG ratio; r = .05344, p = .8332 for plasma
TBARS; r = −.10585, p = .6759 for plasma 8-isoprostane). The brain is
particularly sensitive to oxidative stress, which easily disturbs the
metabolism of neurotransmitters, such as dopamine (Lopresti, 2015).
Dopamine has lots of functions in the brain, including attention regu-
lation (Li et al., 2017). Dysregulation of the dopaminergic system was
found in ADHD patients, including reduced dopamine synthesis, defi-
cient formation, and release of dopaminergic synaptic vesicles, dys-
function of inhibitory dopamine receptors, increased dopamine
reuptake through dopamine transporters, and increased dopamine
degradation by monoamine oxidase (Li et al., 2017). In spite of no cor-
relation between improvements in ADHD symptoms and the elevated
antioxidative capacity by the statistical analysis, it is still desirable to
determine neurotransmitter levels in ADHD patients and clarify the
pathogenic mechanisms related to oxidative stress in future studies as
a reference for clinical treatment.
4.4 | Dietary intake
Dietary intake and eating frequency did not change during the entire
experimental period (Data S1 and S2). That is to say, the appetite and
eating habits of ADHD participants were not influenced by the pla-
cebo or PE supplements.
Compared to the dietary reference intake (DRI) of Taiwan, lower
intake levels of carbohydrates, vitamin C, calcium, and iron, and higher
intake levels of protein, fat, vitamin B6, and vitamin A were found in
ADHD participants (Data S1). Previous research pointed out that die-
tary intake and nutrition-related factors are associated with symptoms
of ADHD, such as an inadequate intake of protein, n-3 fatty acids,
iron, zinc, and magnesium (Millichap & Yee, 2012) and the excess
intake of refined sugar, artificial food coloring, and preservatives
(McCann et al., 2007). Holton and Nigg found that children with
ADHD (n = 184) had unhealthy dietary behaviors, such as consuming
less than two cups of water per day and higher intake of sugary drinks
than children without ADHD (n = 104) (Holton & Nigg, 2016). Another
study also found that Australian children with ADHD were more likely
to have a diet high in saturated fatty acids and low in dietary fiber
(Howard et al., 2011). Nutrient insufficiency may affect
neurocognitive abilities through different pathways, such as iron as a
coenzyme of dopamine and norepinephrine, and zinc as an endoge-
nous neuromodulator in synaptic transmission (Takeda, 2001). There-
fore, determining food consumption and dietary patterns of ADHD
children may be helpful in clarifying relationships between nutritional
factors and ADHD symptoms.
4.5 | Neuropsychological functions and the
antioxidative status before cross-over
The effects of PE supplements on SNAP-IV, CPT-III and antioxidative
status before cross-over were also discussed. There are seven partici-
pants in PE group and 13 participants in placebo group during the first
4 weeks. There was no difference on SNAP-IV, CPT-III, and
antioxidative status between two groups at the beginning of the
study. After 4 weeks, the SNAP-IV, CPT-III and plasma 8-isoprostane
level did not change, however, plasma TBARS level was significantly
decreased in PE group (3.1 ± 1.0 μM for PE group, 8.8 ± 5.6 μM for
placebo group, Wilcoxon rank-sum test, p = .011). The antioxidative
effects of PE have been observed after the first intervention period.
4.6 | Strengths and limitations
This is the first study to evaluate improvements in ADHD symptoms
using both an administered questionnaire and quantitative analyses
after PE. Moreover, all ADHD participants have not psychiatric
HSU ET AL.
comorbidities and did not receive any medication. However, the pre-
sent study still has several limitations. The sample size was quite small
because of the strict screening process and several assessments. Sec-
ond, compliance of taking the supplement was 77.8%, which should
be increased in future studies. The reason of non-compliance was
neglect due to busyness or without supervision. Third, the type of
supplement might be revealed by the participants themselves due to
differences in taste and color, even though the study was designed as
a double-blind experiment. Lastly, the similar trend did not be
observed between plasma TBARS and 8-isoprostane levels, other oxi-
dative damage biomarkers should be measured in future study, includ-
ing oxidative DNA damage, antioxidative enzymes, TOS, TAS, TAC,
and so forth (Hermans et al., 2007).
5 | C O N CL U S I O N S
This study indicated that 4-week supplementation with PE signifi-
cantly decreased the SNAP-IV parent and teacher ratings and the
commission score of the CPTIII, which represent improvements in
inattention and impulsivity in ADHD participants. In addition, reduc-
tion of oxidative stress was also observed based on increased erythro-
cytic GSH/GSSG ratio and decreased plasma TBARS levels in ADHD
participants after 4-week supplementation with PE. However, further
research is needed to determine whether there was any correlation
between the improvement of ADHD symptoms and a reduction of
oxidative stress.
ACKNOWLEDGMENTS
We appreciate DRT (Dax Cedex, French) and Formosa Produce Cor-
poration (New Taipei City, Taiwan) for supplying the pine bark extract.
We also thank Dr. Yannick Piriou who provided the professional infor-
mation and analyzed the composition of the pine bark extract.
CONF LICT S OF INTE R ES T
The authors declare no conflicts of interests associated with this pub-
lication. Neither Formosa Produce Corporation (Taipei, Taiwan) nor
DRT (Dax Cedex, French) has any further role in study design; in the
collection, analysis and interpretation of data; in the writing of the
report; and in the decision to submit the paper for publication.
ORCID
Suh-Ching Yang https://orcid.org/0000-0002-1579-2165
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SUPPORTING INF ORMATION
Additional supporting information may be found online in the
Supporting Information section at the end of this article.
How to cite this article: Hsu C-D, Hsieh L-H, Chen Y-L, et al.
Complementary effects of pine bark extract supplementation
on inattention, impulsivity, and antioxidative status in children
with attention-deficit hyperactivity disorder: A double-blinded
randomized placebo-controlled cross-over study. Phytotherapy
Research. 2021;1–10. https://doi.org/10.1002/ptr.7036