JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY

Volume 28, Number 5, 2018

ª Mary Ann Liebert, Inc.
Pp. 331–338
DOI: 10.1089/cap.2017.0157

l-Carnosine as Adjunctive Therapy in Children

and Adolescents with Attention-Deficit/Hyperactivity Disorder:
A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Alireza Ghajar, MD,* Farinaz Aghajan-Nashtaei, MD,* Mohsen Afarideh, MD-MPH,

Mohammad-Reza Mohammadi, MD, and Shahin Akhondzadeh, PhD

Abstract
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Objectives: This study aimed to investigate the efficacy and tolerability of l-carnosine as an add-on to methylphenidate in
management of children with attention-deficit/hyperactivity disorder (ADHD).
Methods: This was an 8-week, randomized, double-blind placebo-controlled study. Fifty-six drug-free children and ado-
lescents aged 6–17 years old with a diagnosis of ADHD entered the study. The patients were randomly assigned to l-carnosine
(800 mg/d in two divided doses) or placebo plus methylphenidate (0.5–1.5 mg/kg/d) for 8 weeks. Children were assessed
using the Teacher and Parent ADHD Rating Scale-IV (ADHD-RS-IV) at baseline and at weeks 4 and 8 postbaseline.
Results: Fifty patients completed the study, and all had two postbaseline measurements. Using the general linear model
repeated measures, significant effect was observed for time · treatment interaction on total and inattention subscales of the
Parent ADHD-RS (Greenhouse-Geisser corrected: F = 3.783, df = 1.444, p = 0.041 and F = 4.032, df = 1.600, p = 0.030).
Improvements in the Teacher ADHD-RS were not significantly different between the two groups in total (Greenhouse-
Geisser corrected: F = 0.200, df = 1.218, p = 0.705), as well as inattention and hyperactivity subscale scores ( p = 0.956 and
0.281, respectively). The frequency of side effects was not significantly different between the two treatment arms.
Conclusions: l-carnosine, as a supplementary medication, might be beneficial in treatment of children with ADHD. How-
ever, further investigations and different doses of l-carnosine are required to replicate these findings in children with ADHD.

Keywords: ADHD, GABA modulatory, l-carnosine, NMDA receptor

Introduction neurotransmitter systems are becoming of interest for development

of effective treatments for refractory ADHD patients (Durrant and

A ttention-deficit/hyperactivity disorder (ADHD) rep-

resents a neurodevelopmental condition affecting 3%–7% of
children and is characterized by age-inappropriate inattentiveness
and increased hyperactivity and impulsivity (Taylor et al. 2004;
Fayyad et al. 2007; Willcutt 2012). ADHD is presumably associ-
ated to imbalance of catecholamine metabolism in the cerebral
cortex and dysregulation of dopaminergic and noradrenergic neural
circuits (Millichap 2008; Bauer et al. 2016). Treatment of ADHD
focuses on administration of stimulants, including methylphenidate
(Banaschewski et al. 2004). These stimulants produce complete
remission in about only 30% of cases, and about 10%–30% of
patients with ADHD may not respond to stimulants or may not be
able to endure potential adverse events, including reduced appetite,
sleep disturbances, mood lability, and exacerbation of comorbid tic
disorders (Banaschewski et al. 2004; Steele et al. 2006). Since all
cases cannot be attributed to one mechanism (Pliszka 2005), further
Heresco-Levy 2014). Glutamate is the primary excitatory neuro-
transmitter found in the brain (Pittenger et al. 2011), essential in
frontostriatal transmission and often co-transmitted with dopamine
(Chuhma et al. 2009). Cortical glutamatergic activity is demon-
strated to be decreased in some ADHD cases (Durrant and Heresco-
Levy 2014). Moreover, dopaminergic and glutamatergic system
neurotransmission studies and genetic evaluations have suggested
involvement of the NMDA receptor dysregulation in ADHD
pathophysiology (Kotecha et al. 2002; Turic et al. 2004). Alto-
gether agents with effects on the dopamine and glutamate path-
ways, NMDA receptor, and GABA modulators are of interest as
probable medications for ADHD treatment.
There is growing evidence for the use of Complementary or
Alternative Medicines (CAMs; e.g., l-carnosine) in different neu-
ropsychiatric disorders (Sarris et al. 2011; Ghajar et al. 2016).
Evidence indicated that more than half of the children diagnosed

Psychiatric Research Center, Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Iran.
Funding: This study was supported by a grant from Tehran University of Medical Sciences to S.A. (Grant No. 29573).
*Both these authors contributed equally to this work.

331
 332
with ADHD are treated with one or more CAMs by their parents
(Chan et al. 2003). Therefore, evidence is required to support
claims for efficacy of this treatment in this vulnerable group (Sarris
et al. 2011). For those patients who cannot tolerate or have limited
response to stimulants, or families who simply prefer nonstimulant
therapy, finding new nonstimulus medicines and supplements that
affect the disorder is essential (Greenhill et al. 2002; Banaschewski
et al. 2004; Curtis and Patel 2008; Sarris et al. 2011).
One example of the supplements used is l-carnosine, a dipeptide
of the b-alanine and l-histidine known as an antiaging, antioxidant,
and neuroprotective compound, found in high concentrations in the
brain tissue (Wang et al. 2000; Prokopieva et al. 2016). Carnosine,
co-localized at glutamatergic synapses (Sassoè-Pognetto et al.
1993), is indicated to decrease glutamate levels, inhibit glutamate
release, and is postulated as an NMDAR and GABA modulating
agent (Shen et al. 2007, 2010; Brondino et al. 2016; Ouyang et al.
2016). Carnosine accumulates in the subfrontal cortex and may
enhance the frontal lobe function (Trombley et al. 1998; Chez et al.
2002), the area of scientist’s interest in ADHD patients. Particular
characteristics of l-carnosine consist of being highly bioavailable,
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penetrable through the blood–brain barrier with few side effects,
and no danger of overdose make it a drug of interest between CAMs
(Prokopieva et al. 2016).
In this 8-week, double-blind placebo-controlled trial, we aimed
to assess the efficacy of l-carnosine adjuvant to methylphenidate in
treatment of children with ADHD. To the best of our knowledge,
this study is the first double-blind and placebo-controlled clinical
trial assessing the adjunctive role of l-carnosine in patients with
ADHD.
Materials and Methods
Trial design and setting
This study was an 8-week, randomized, parallel group, double-
blind placebo-controlled trial undertaken by outpatients at the
Roozbeh Psychiatric Hospital affiliated with Tehran University of
Medical Sciences (TUMS) during March 2016 to July 2017. The
protocol was approved by the Institutional Review Board (IRB) of
TUMS (Grant No. IR.TUMS.REC.1394.1290) and was in accor-
dance with the Declaration of Helsinki and its successive revisions.
After a complete description of the procedures and the purpose of
the study, written informed consent was obtained from each pa-
tient’s parent or their legal guardian. The trial was registered in the
Iranian registry of clinical trials (www.irct.ir; trial identifier with
the IRCT database: IRCT201601031556N84).
Participants
Subjects who initiated the study were newly diagnosed (drug
naive) outpatient boys and girls aged 6–17 years who met the Di-
agnostic and Statistical Manual of Mental Disorders, Fifth Edition
(DSM-5) criteria for ADHD supported by Kiddie Schedule for
Affective Disorders (KSADS) (Ghanizadeh et al. 2006) and a
medical history. Children were excluded if they had been previ-
ously diagnosed with a psychiatric comorbidity except for oppo-
sitional defiant disorder (ODD). Other exclusion criteria were
history or current diagnosis of pervasive developmental disorders,
mental retardation (defined as intelligence quotation below 70);
any evidence of suicide risk, receiving l-carnosine in the last 3
weeks; history of allergy to l-carnosine or methylphenidate (Rita-
line); presence of any medical problem; presence of uncontrolled
seizures; systolic blood pressure more than 120 mm Hg; resting pulse
GHAJAR ET AL.
rate <60/min or >115/min; receiving any supplement or medication
for ADHD or other psychotropic medications; and current abuse or
dependence on drugs within 6 months. It was declared to each patient
and their guardian that they were free to withdraw from the trial
without any negative effect on their treatment.
Randomization, allocation concealment, and blinding
Patients were randomly assigned to treatment groups in a 1:1
ratio using a computer-generated code. The assignments were kept
in sealed, opaque, and stapled envelopes with an aluminum foil
inside each envelope to make the content of the envelope unrec-
ognizable in intense light until data analysis. l-carnosine and pla-
cebo were encapsulated and were identical. The person dispensing
the drug, the patient, the physician who referred the patient, the
rater, and the statistical analyzer were all blinded to allocation.
Intervention
Eligible subjects were randomly assigned to receive methyl-
phenidate hydrochloride (MPH; Ritaline; 0.5–1.5 mg/kg) plus ei-
ther l-carnosine (ACER) 800 mg/d or Placebo for an 8-week trial.
Methylphenidate was titrated up during the trial according to the
following schedule: 10 mg/d (two divided doses) for the first week
followed by 20 mg/d (two divided doses) from the second week till
the rest of the trial. Patients who weighed more than 30 kg received
30 mg/d (three divided doses) from the third week of the study.
Medication adherence was measured by comparison of weekly
tablet counts with participant reports of medication intake to esti-
mate the proportion of dispensed medication that was actually
ingested.
Outcome
The principal measure of outcome was the Teacher and Parent
ADHD Rating Scale-IV (ADHD-RS-IV) (Dupaul et al. 1998; Pappas
2006) that has been used extensively in Iran in school-age children
and provides valid measures of behavioral abnormality and attention
(Akhondzadeh et al. 2004; Salardini et al. 2016). The primary out-
come measure was change in scores of the parent version of ADHD-
RS-IV from baseline to week 8 in each group. Secondary outcome
measures were change in scores of the teacher version of ADHD-RS-
IV and response rate in each group.
Safety
Side effects were systematically recorded throughout the study
and were assessed using a checklist composed of 25 side effects,
including psychological, neurologic, autonomic, and other side
effects (Noorbala et al. 1999; Akhondzadeh et al. 2000; Mod-
abbernia et al. 2012). There were no early dropouts due to early
adverse events in this trial. Parents and children were asked to
immediately inform the research team in case of any unexpected
symptom or complaint during the study period.
Sample size
A minimal sample size of 50 (25 patients in each group) was
calculated based on the assumption of a clinically significant dif-
ference of 4 on the Teacher and Parent ADHD-RS, a standard
deviation of 5 on the Teacher and Parent ADHD-RS (according to
the pilot study), a power of 90%, and a two-sided significance level
of 0.05. Assuming a 10% attrition rate, a total sample size of 56 was
estimated.
 L-CARNOSINE AS AN ADJUNCT TO METHYLPHENIDATE IN ADHD
Statistical analyses
Statistical Package of Social Science Software (SPSS version
22; IBM Company) was used to carry out the statistical analysis.
General linear model (GLM) repeated measure was used to
compare Teacher and Parent ADHD-RS scores between treatment
groups during the study course. A two-way repeated measures
analysis of variance (time–treatment interaction) was used. The two
groups were considered as a between-subject factor, and the three
measurements during treatment were counted as within-subject
factor. This was done for the Teacher and Parent ADHD-RS scores.
A traditional ‘‘observed cases’’ (OC, the patients who completed
the trial) analysis at 8 weeks was the primary efficacy analysis. In
addition, intention to treat analysis with the last observation carried
forward procedure was also performed. To estimate the effect size
for the two outcome measures, we calculated the partial eta squared
(g2) in the repeated measures GLM analysis.
Results
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Baseline characteristics of the patients
From a total of 98 children screened for the trial, 56 were ran-
domly assigned to receive either l-carnosine (n = 28) or placebo
(n = 28) in 2 trial arms. Fifty patients completed the study, and all
had two postbaseline measurements. Three patients in the l-
carnosine (withdrawn consent) and three patients in the placebo
group (withdrawn consent) dropped out, all before week 4 (Fig. 1).
However, all 6–17-year-old individuals were considered in the
inclusion criteria; in the final population we had 6–13-year-old
participants. As demonstrated in Table 1, baseline characteristics of
the patients were not significantly different between the two trial
arms (Table 1). There was no significant difference in terms of
baseline total and subscales of Parent and Teacher ADHD-RS
scores between the two treatment arms.
FIG. 1. Flow diagram representing case selection for the trial program.
333
The Parent ADHD-RS
The GLM analysis of repeated measures revealed significant
effects for time (Greenhouse-Geisser corrected: F = 430.638,
df = 1.444, p < 0.001) and treatment (between-subject factor;
Greenhouse-Geisser corrected: F = 4.556, df = 1, p = 0.038) inter-
actions on the total Parent ADHD-RS scores. The effect of
time · treatment interaction was also significant (Greenhouse-
Geisser corrected: F = 3.783, df = 1.444, p = 0.041) over the trial
period of 8 weeks, showing that the behavior of two treatment
groups was different across time on the total Parent ADHD-RS
scores (Fig. 2). Partial g2 of 0.073 was calculated for total Parent
ADHD-RS score. Similarly, the two-factor repeated measure
analysis of variance (ANOVA) demonstrated significant effects of
time (Greenhouse-Geisser corrected: F = 391.135, df = 1.600,
p < 0.001) and time · treatment interaction (Greenhouse-Geisser
corrected: F = 4.032, df = 1.600, p = 0.030) for the inattention scale
over the study period (Fig. 3). Partial g2 of 0.077 was calculated for
inattention subscale scores. The results of the two-factor repeated
measure ANOVA showed a significant effect of time on the
changes in hyperactivity scale scores (Greenhouse-Geisser cor-
rected: F = 297.707, df = 1.332, p < 0.001). However, the effect of
time · treatment interaction term was not significant, showing that
the behavior of both treatment groups was similar on the hyper-
activity subscale across time (Greenhouse-Geisser corrected:
F = 2.453, df = 1.332, p = 0.113).
The Teacher ADHD-RS
The GLM analysis of repeated measures revealed significant
effects for time (Greenhouse-Geisser corrected: F = 14.994,
df = 1.218, p < 0.001), but not for treatment (between-subject fac-
tor; Greenhouse-Geisser corrected: F = 0.240, df = 1, p = 0.626), or
the time · treatment interaction term (Greenhouse-Geisser cor-
rected: F = 0.200, df = 1.218, p = 0.705) over the trial period of
 334 GHAJAR ET AL.

Table 1. Baseline Characteristics of Patients

According to Treatment Groups

MPH+l-carnosine MPH+placebo
Baseline variable (n = 25) (n = 25) p

Age, years 9.12 – 2.18 8.28 – 1.59 0.128

(mean – SD)
Gender, male (%) 21 (84) 19 (76) 0.725a
Family history, 9 (36) 5 (20) 0.345a
positive (%)
Ethnicity All the patients were 1.000
Persian
Type of ADHD All had combined subtype 1.000
of ADHD
a
Indicates the p-value reported by Fisher exact test.
ADHD, attention-deficit/hyperactivity disorder; MPH, methylphenidate
hydrochloride; SD, standard deviation.

8 weeks for the total Teacher ADHD-RS score (Fig. 4). Similarly,
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repeated measure ANOVA demonstrated no significant effect for

the time · treatment interaction term for inattention (Greenhouse-
Geisser corrected: F = 0.012, df = 1.323, p = 0.956) and hyperactivity
(Greenhouse-Geisser corrected: F = 1.231, df = 1.186, p = 0.281)
scale scores.
FIG. 3. Repeated measure for comparison of the effects of two
treatment groups on Parent ADHD Inattention Rating Subscale
Adverse events scores. Values represent mean – SEM.

Seven side effects were recorded during the course of the study
(Table 2). No serious adverse event was observed in any of the
patients. The most common side effects were abdominal pain
(28%), headache (20%), and insomnia (16%) in the l-carnosine
group and abdominal pain (24%) and headache (24%) in the
placebo group. Frequency of side effects did not differ significantly
between the two groups (Table 2).

FIG. 2. Repeated measure for comparison of the effects of two
treatment groups on Total Parent ADHD Rating Scale score. Values
represent mean – SEM. ADHD, attention-deficit/hyperactivity dis-
order; SEM, standard error of the mean.
Discussion
The results of the present study support the short-term beneficial
effects of l-carnosine as an adjuvant treatment in patients with
ADHD. The results demonstrated improvements in the total score
and the inattention subscale of the Parent ADHD-RS compared to
placebo. However, the p-values reported in the GLM analysis were
not robust (0.04 and 0.03). The effect size was calculated as partial
g2 of 0.073 and 0.077 for total and inattention subscale scores,
respectively. Improvements in the Teacher ADHD-RS were not
significantly different between the two groups, most likely because
of the overcrowded classrooms in developing countries like Iran,
which resulted in teachers not being able to dedicate enough time to
consider and follow each student’s behavior. However, it is also
plausible that no effect was identified from teachers because of
little add-on benefits of l-carnosine. To the best of our knowledge,
this is the first placebo-controlled survey of l-carnosine supple-
mentation in patients with ADHD.
One of the possible mechanisms of the observed beneficial ef-
fects of l-carnosine on ADHD symptoms could be through its role
as an NMDA receptor regulator. NMDA receptor modulators show
satisfactory improvements in neuropsychological disorders such as
depression and autism (Ghaleiha et al. 2013; Jafarinia et al. 2016;
Hajizadeh-Zaker et al. 2017). Among hypotheses for ADHD, dys-
function of NMDA-type glutamate receptors has recently been
suggested by accumulating genetic and animal studies (Lehohla
et al. 2004; Elia et al. 2012; Pei-Chen Chang et al. 2014). The
provided initial evidence suggests elevation of glutamate levels in
 L-CARNOSINE AS AN ADJUNCT TO METHYLPHENIDATE IN ADHD 335

Another possible explanation for the observed beneficial effects

of l-carnosine could be its GABA-modulatory activity (Trombley
et al. 1998). GABA and glutamate have critical roles in inhibitory
and excitatory neurotransmission, respectively (Brennan and Arn-
sten 2008); and alterations in the interactions among glutamate,
GABA, and dopamine neuronal circuits are likely to be involved in
the pathophysiology of ADHD (Durrant and Heresco-Levy 2014).
It is reported that GABA concentration was reduced in primary
motor cortex of ADHD children (Edden et al. 2012) with correla-
tions with impulsive and aggressive behavior (Silveri et al. 2013).
Carnosine is a GABA modulating agent (Brondino et al. 2016),
which increases the extracellular GABA level (Ouyang et al. 2016)
possibly by modifying homocarnosine levels or by a direct che-
lating effect on zinc at GABA receptor sites (Ozonoff et al. 1991).
Interestingly, there is no common idea regarding increase or de-
crease of Glx (combination of glutamate, glutamine, and GABA) in
different areas of brain in patients with ADHD (Naaijen et al.
2015). Some studies showed decrease (Perlov et al. 2007; Drams-
dahl et al. 2011). Some studies found increased Glx in striatal areas
(Carrey et al. 2007; Hammerness et al. 2012), which seemed to
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decline after treatment with MPH (Carrey et al. 2002, 2003).

Another possible explanation for the observed beneficial effects
of l-carnosine could be its antioxidant activity (Boldyrev et al.
2013). Inflammation is becoming a therapeutic target for neu-
FIG. 4. Repeated measure for comparison of the effects of two ropsychological disorders, including depression and ADHD (Lo-
treatment groups on Total Teacher ADHD Rating Scale scores. Va- presti 2015; Alamdarsaravi et al. 2017). ADHD is indicated to be
lues represent mean – SEM. associated with increased oxidative stress in a recent meta-analysis,
although findings are inconsistent ( Joseph et al. 2015; Lopresti
2015). Pinus marinus (French maritime pine bark) and zinc both
the prefrontal cortex and anterior cingulate cortex (ACC) of patients have strong antioxidant activities and have support for treatment of
with ADHD (Carrey et al. 2003; Kavirajan 2009), which may in- ADHD in randomized, double-blind placebo-controlled studies
crease NMDA glutamate receptor activity with a positive correla- (Akhondzadeh et al. 2004; Trebatická et al. 2006). l-Carnitine’s
tion between this glutamatergic dysregulation and impulsivity and antioxidant activity is mediated through different mechanisms,
hyperactivity symptoms (Bauer et al. 2016). Carnosine inhibits including reactive oxygen species and peroxyl radical scavenging
glutamate release and protects against NMDA-induced neurotox- and metal ion chelation (Boldyrev et al. 2013).
icity (Shen et al. 2007). The present study was in line with previous reports regarding the
Memantine, an NMDA receptor antagonist, provides improve- role of anti-inflammatory agents and GABA-modulatory and
ment in symptoms of both children and adults with ADHD (Findling NMDA receptor antagonists in treatment of ADHD, but the re-
et al. 2007; Surman et al. 2013; Biederman et al. 2017). Interestingly, sponse was not satisfactory enough may be because a low dose of
Atomoxetine, an approved ADHD treatment that is supposed to bind l-carnosine was used in this trial. In one of our recent unpublished
to the presynaptic noradrenaline transporter (NET), is found to block trials, we treated chronic schizophrenia patients with a dose of 2 g/d
NMDA receptors (Ludolph et al. 2010). In a 6-week clinical trial, of l-carnosine, and this yielded satisfying results and a good tol-
Sarcosine, a glycine transporter-1 inhibitor (modulating the gluta- erability profile. Around medium effect sizes and not seeing sig-
matergic neurotransmission system through activating NMDA-type nificant effects in teacher scales indicated that decisive conclusion
glutamate receptors) induced significant improvements in ODD about the l-carnosine efficacy in individuals with ADHD needs
symptoms of children with ADHD (Tzang et al. 2016). further investigations.
Even though the present study has several strengths such as the
double-blind placebo-controlled design and the rigorous adjust-
Table 2. Frequency of Adverse Events ment for baseline clinical variables, various limitations should
in the Study Groups be addressed to prevent overgeneralization of the findings. First, the
population size was relatively small. Second, the follow-up pe-
MPH+l-carnosine MPH+placebo
Adverse event (n = 25), n (%) (n = 25), n (%) pa riod was relatively short to make the accurate long-term effects of
l-carnosine clear. The patient nutritional condition was not eval-
Headache 6 (24.0) 5 (20.0) 1.000 uated at admission although alteration of plasma amino acid levels
Abdominal pain 6 (24.0) 7 (28.0) 1.000 might not correlate with nutritional status (Jackson and Garrod
Insomnia 4 (16.0) 4 (16.0) 1.000 1978). Finally, absence of functional and cognitive assessments
Constipation 4 (16.0) 4 (16.0) 1.000 (e.g., Clinical Global Impressions) and cognitive measurement of
Sweating 3 (12.0) 3 (12.0) 1.000 attention are other limitations of the present study. However, a
Nausea 3 (12.0) 3 (12.0) 1.000 consistent relationship between ADHD-RS-IV scores and Clinical
Vomiting 1 (4.0) 1 (4.0) 1.000
Global Impression (CGI) levels was reported (Goodman et al.
a
p Value is reported using the Fisher exact test. 2010). We conducted this trial on all newly diagnosed ADHD pa-
MPH, methylphenidate hydrochloride. tients; however, including only the treatment-resistant patients might
 336
have led to more convincing outcomes through purifying the trial
arms from children who are responders to common stimulant
medications.
Conclusion
The results of this study must be considered preliminary. Eight
weeks of treatment with l-carnosine (800 mg/d) as an add-on to
methylphenidate appeared to be safe and well tolerated. Mean-
ingful beneficial effects on the Parent ADHD-RS scores of patients
with ADHD were indicated although no significant effect was de-
tected on the Teacher ADHD-RS. Efficacy and tolerability of
l-carnosine in higher doses and longer treatment periods, as well as
in female-predominant populations, are still unclear and may be
appropriate targets for further investigation.
Clinical Significance
To the best of our knowledge, there is lack of evidence on the
efficacy of l-carnosine add-on to methylphenidate in patients with
ADHD. Results from this trial indicate that l-carnosine can be
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considered as an effective adjuvant therapy in ADHD.
Disclosures
The authors declare no conflicts of interest.
Acknowledgments
This study was the postgraduate thesis of F.A.-N. toward the
Iranian Board of Psychiatry under supervision of S.A. This study
was supported by a grant from TUMS to S.A. (Grant No. 29573).
The funding organization had no role in the design and conduct of
the study; in the collection, analysis, and interpretation of the data;
or in the preparation, review, or approval of the article and the
decision to submit the article for publication.
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