Advances in Integrative Medicine 9 (2022) 37–43

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Advances in Integrative Medicine

journal homepage: www.elsevier.com/locate/aimed

Original Research Paper

Efficacy and safety of saffron as adjunctive therapy in adults with

attention-deficit/hyperactivity disorder: A randomized, double-blind, ]]
]]]]]]
]]

placebo-controlled clinical trial

Benyamin Pazoki 1, Nadia Zandi 1, Zeinab Assaf 1, Hossein Sanjari Moghaddam,
⁎
Arefeh Zeinoddini, Mohammad Reza Mohammadi, Shahin Akhondzadeh
Psychiatric Research Center, Roozbeh Hospital, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran

a r t i cl e i nfo a bstr ac t

Article history: Objective: Around 30% of patients with Attention-Deficit/Hyperactivity Disorder (ADHD) do not respond to
Received 11 June 2020 Ritalin or cannot tolerate its side effects, which necessitates the consideration of alternative options.
Received in revised form 10 August 2021 Previous studies have shown the beneficial effects of Crocus sativus (saffron) in children with ADHD.
Accepted 9 January 2022
However, its potential therapeutic effects in adults with ADHD is unknown. This study aimed to evaluate the
Available online 11 January 2022
efficacy and safety of saffron as an adjuvant to Ritalin for improving symptoms in adults with ADHD.
Design: This was a randomized, double-blind, placebo-controlled clinical trial.
Keywords:
Saffron Methods: Fifty-six patients diagnosed with ADHD were assigned into two parallel groups to receive Ritalin
Attention-deficit/hyperactivity disorder (30 mg/day) plus placebo or Ritalin plus saffron (15 mg twice daily) for six weeks. The patients were as­
Ritalin sessed with Conners' Adult ADHD Rating Scales (CAARS) and the Adult ADHD Self-Report Scale (ASRS) at
Crocus sativus baseline, week 3 and week 6.
Results: Forty-four patients completed the trial. GLM repeated-measure analysis demonstrated significant
time × treatment interaction effect for ASRS (df=2, F=3.455, and P-value=0.036) and CAARS (df=1.584,
F=3.939, and P-value=0.033) score from baseline to the study endpoint. We found a significantly greater
reduction in ASRS scores in the saffron group compared with the placebo group from baseline to the study
endpoint (week 6) (P-value=0.024). However, the change score from baseline to week 3 was not sig­
nificantly different between trial groups (P-value=0.269). There was no significant difference in the im­
provement of CAARS scores between saffron and placebo from baseline to week 3 or 6 (P-value=0.564 and
0.089, respectively). There was no significant difference between the two groups in baseline parameters and
frequency of side effects.
Conclusions: Saffron combination therapy with Ritalin can effectively improve symptoms of patients with
ADHD. However, further studies with larger sample sizes and longer follow-up treatment are needed to
confirm our findings.
This trial was registered with the Iranian Registry of Clinical Trials (www.irct.ir; No
IRCT20090117001556N111).
© 2022 Elsevier Ltd. All rights reserved.

1. Introduction
Attention-deficit/hyperactivity disorder (ADHD) is a mental-be­
havioral disorder categorized by impulsive behavior, hyperactivity
and inattentiveness that affects 4% of adults in various aspects of
⁎
Correspondence to: Psychiatric Research Center, Roozbeh Psychiatric Hospital,
Tehran University of Medical Sciences, South Kargar Street, Tehran 13337, Iran.
E-mail address: s.akhond@neda.net (S. Akhondzadeh).
1
The first Three Authors contributed equally into this study.
personal and social life [1,2]. Studies have indicated the negative
impact of ADHD on academic and occupational performance, family
relationships, self-esteem and functional ability [3–6]. The main
underlying molecular mechanisms of ADHD are impaired dopami­
nergic and noradrenergic transmission [7]. Treatment of ADHD in­
cludes medication or behavioral therapy and a combination of both,
which is documented to be more effective [8,9]. The most common
pharmacological choice for managing ADHD symptoms is methyl­
phenidate (Ritalin) by inhibiting dopamine transporters and in­
creasing the dopamine level in the neuronal synapses [10,11].
Although Ritalin modifies the ADHD symptoms and improves

https://doi.org/10.1016/j.aimed.2022.01.002
2212-9588/© 2022 Elsevier Ltd. All rights reserved.
B. Pazoki, N. Zandi, Z. Assaf et al.
cognitive deficits, it fails in some cases or associates with adverse
effects like nausea, insomnia, transient headache, low appetite and
behavioral rebound [8,12–15]. In this regard, several studies have
focused on non-stimulant drugs as an alternative for ADHD treat­
ment with fewer adverse effects. Among all medications, anti­
depressants were effective in treating ADHD [16] such as Bupropion
in comparison with Ritalin [17,18]. Despite the potency of anti­
depressants, the side effects like orthostatic hypotension, antic­
holinergic effects and arrhythmias limited their prescription [19].
Moreover, the use of stimulants such as Ritalin for the treatment of
ADHD is often believed to cause dependence on stimulants or lead to
a predisposition to the use of substances later on in life. Therefore,
alternative approaches including non-stimulant agents and herbal
medicine might be preferred by patients and their parents.
The use of alternative approaches, particularly herbal medicine
for the treatment of various disorders dates back to hundreds of
years ago. Herbal medicine is more readily accepted among popu­
lations worldwide due to cultural backgrounds and their safety
profile compared to undesirable side effects of approved drugs [20].
More importantly, natural products or herbs are often fertile ground
for discovering new drug candidates and the development of
modern medicines [21]. For instance, Hypericum perforatum (more
commonly known as St John's wort) is commonly used throughout
Europe and has well-demonstrated antidepressant effects [22].
Crocus sativus is a traditional plant known for its culinary, coloring
and medicinal features in Asian and European countries for years.
The dried part of Crocus sativus (stigma), named saffron, possess the
main role in the treatment of many diseases. The important bioac­
tive constituents of saffron include Crocin, Picrocrocin, Safranal and
Crocetin which are responsible for the intense red-orange color,
bitter taste and odor, respectively [23] and have been considered as
neuroprotective components [24]. Based on recent studies, saffron
has antitumor, antispasmodic, antihypertensive, antiatherogenic,
anticoagulant [25], antiseptic, antidepressant and anticonvulsant
properties [26]. Interest in the evaluation of saffron's impact in the
central nervous system (CNS) is increasing. Hence, saffron has been
shown to be comparable to fluoxetine and imipramine for the
treatment of mild to moderate depression [19,27–30]. Con­
comitantly, saffron components enhance the inhibition of dopamine
and norepinephrine reuptake and play a role as N-methyl-D-aspartic
acid receptor antagonist and GABA-α agonists [31]. Likewise, there is
various evidence about saffron improving memory and ameliorating
anxiety and depression [32,33]. Saffron is believed to be of value as
an antidepressant, and antidepressants have evident effects in im­
proving ADHD symptoms [34,35].
In this randomized, double-blinded, placebo-controlled clinical
trial, we aimed to investigate the beneficial effects of saffron as an
adjunctive treatment with Ritalin in adults with ADHD.
2. Methods
2.1. Trial design and settings
This is a randomized, double-blind, placebo-controlled clinical
trial, conducted on adults with ADHD at the outpatient psychiatric
clinic of Roozbeh Hospital (Tehran University of Medical Sciences,
Tehran, Iran) from July 2018 to February 2020. This study was ap­
proved by the institutional review board (IRB) and the ethics com­
mittee of Tehran University of Medical Sciences
(IR.TUMS.VCR.REC.1397.259). Also, this study was in accordance with
the Declaration of Helsinki and its subsequent revision. All patients
provided written informed consent, being aware of the procedure
and purpose of the study and the possibility of leaving the trial and
returning to their standard treatment without any problem con­
cerning their relationship with their physician. Clinical examinations
of patients were conducted on four separate sessions: baseline, week
38
Advances in Integrative Medicine 9 (2022) 37–43
3, and week 6. This trial is registered at the Iranian registry of clinical
trials (www.irct.ir; registration number: IRCT20090117001556N111).
2.2. Participants
The trial participants were adults aged 20–60 years with a di­
agnosis of ADHD based on the Diagnostic and Statistical Manual of
Mental Disorders, 5th Edition (DSM-5) and the Kiddie Schedule for
Affective Disorders and Schizophrenia (KSADS) [36]. The exclusion
criteria of the trial were: (1) intelligence quotient lower than 70; (2)
chronic medical disease including seizure, cardiovascular disease,
and organic brain disease; (3) presence of other major psychiatric
disorders such as bipolar disorder and major depression; (4) history
of tic disorder; (5) substance dependence (except for nicotine and
caffeine) during past six months; (6) receiving any psychotropics
drugs during past two weeks; (7) receiving psychostimulants or
atomoxetine during past three months; (8) lactating or pregnant
women; and (9) history of suicide attempt, psychosis or aggres­
siveness.
2.3. Interventions
Patients with ADHD were randomly assigned (1:1) either to the
placebo or the saffron group. Both groups received 30 mg/day me­
thylphenidate hydrochloride (MPH; Ritalin; Novartis, Switzerland)
divided into two separate doses at 30 min before breakfast and lunch
for six weeks. In addition to Ritalin, the saffron group received 15 mg
of saffron capsules (ACER, Tehran, Iran) twice daily, while the pla­
cebo group received placebo capsules. No other psychiatric medi­
cation was administered during this course. Medication adherence
was controlled by pill-counting and patient reports of medication
intake.
2.4. Outcome and safety
All participants were assessed using the Adult ADHD Self‐Report
Scale (ASRS) [37] and the Conners' Adult ADHD Rating Scales-self
report: screening version (CAARS) [38] at baseline and weeks 3 and
6. Two raters with good experience in executing the ASRS and CAARS
and acceptable inter-rater reliability [intraclass correlation coeffi­
cient = 0.90], were in charge of rating the patients. The ASRS is the
official and most commonly used instrument for the assessment of
adult ADHD patients. The CAARS is a 26-item questionnaire for the
assessment of ADHD symptoms in persons aged ≥ 18 years. Side
effects of treatments were recorded at each visit (baseline and week
3 and 6) through open-ended questioning, followed by a complete
side effect checklist containing general side effects. Moreover, all
patients were asked about any adverse event that was not men­
tioned in the checklist. The ASRS and CAARS were the primary
outcome measures, and the frequency of adverse events was the
secondary outcome measure of this study.
2.5. Sample size
Assuming a clinically significant difference of 4 on the ASRS score
between saffron and placebo groups with a standard deviation (SD)
of 4 (based on our pilot study), a power of 85%, and a two-sided
significance level of 5%, a minimal sample size of 40 was estimated.
Considering an attrition rate of 10%, a total sample size of 50 (25
patients in each group) was planned.
2.6. Randomization, allocation, concealment, and blinding
The trial participants were equally randomized into two
groups of saffron and placebo in a 1:1 ratio. Using the Microsoft
Office Excel software, a specific random code was allocated to
B. Pazoki, N. Zandi, Z. Assaf et al.
Fig. 1. Flow diagram of the study.
each patient. The randomization and allocation were conducted
using block randomization (with blocks of size 4) by the primary
investigator of the study, who was not involved in the diagnosis
and follow-ups. The allocations were kept in confidential and
sealed opaque envelopes and were exposed at the end of the
trial. Separate individuals implemented randomizations, drug
administration, rating, data entry, and statistical analysis. All
participants, the physician who referred the patients, the psy­
chiatrists who conducted the assessments, and the statistician
were blinded to the type of medication. Placebo capsules were
completely indistinguishable from saffron regarding shape, size,
color, and taste. Both saffron and placebo capsules were ad­
ministered by a psychiatry resident.
2.7. Statistical methods
The Statistical Package of Social Science Software (SPSS ver­
sion 20, IBM Company, USA) was used to compare the trial
groups based on the ASRS and CAARS scores and the frequency of
adverse events. Continuous variables were demonstrated as
mean (standard deviation), and categorical variables were dis­
played as frequency (percentage). The Chi-square or Fisher's
Exact tests were applied to compare the categorical variables,
including the frequency of adverse events between two trial
groups at the study endpoint. The general linear model (GLM)
repeated-measures analysis was implemented to explore the
time, treatment, and time × treatment effects. Greenhouse-
Geisser correction for degrees of freedom was reported if
Mauchly's test of sphericity was significant. An independent t-
test (two-tailed) was used to compare the mean change of the
ASRS and the CAARS scores from baseline to each visit (week 3
and 6) between saffron and placebo groups. P-value of < 0.05 was
considered as statistically significant.
39
Advances in Integrative Medicine 9 (2022) 37–43
3. Results
3.1. Participants and baseline characteristics
Fig. 1 illustrates the flow diagram of this trial. A total of 106
ADHD patients were screened against the eligibility criteria, and 56
patients were included and randomized into two parallel groups
receiving either Ritalin plus saffron (n = 28) or Ritalin plus placebo
(n = 28). Within each group, six patients were excluded due to
consent withdrawal (three in the saffron group and six in the pla­
cebo group), substance abuse (two in the saffron group), and emi­
gration from the city (one in the saffron group) (Fig. 1). Table 1
demonstrates the baseline characteristics of patients in two trial
groups. There was no significant between-group difference in age,
gender, and disease duration, family history, marital status, educa­
tion, and smoking (P-value = 0.634, 0.644, 0.198, 0.689, 0.227, 0.520,
and 0.644, respectively). Different types of ADHD were distributed
equally in saffron and placebo groups (20 combined, one inattentive,
and one hyperactive in each group, P-value = 1). Moreover, the
baseline ASRS and CAARS scores were not significantly different
between the saffron and placebo groups (P-value = 0.673 and 0.529,
respectively) (Table 1).
3.2. ASRS scores
GLM repeated-measure analysis demonstrated a significant time
× treatment interaction effect for ASRS score from baseline to the
study endpoint (df=2, F=3.455, and P-value=0.036) (Fig. 2a). Using an
independent t-test, we found a significantly greater reduction in
ASRS scores in the saffron group compared with the placebo group
from baseline to the study endpoint (week 6) (P-value=0.024).
However, the change score from baseline to week 3 was not sig­
nificantly different between trial groups (P-value=0.269). Moreover,
ASRS scores were significantly lower in the saffron group in week 6
B. Pazoki, N. Zandi, Z. Assaf et al. Advances in Integrative Medicine 9 (2022) 37–43

Table 1
Baseline characteristics of the patients in the two trial groups.

Saffron group (n = 22) Placebo group (n = 22) P-value

Age [years; mean (SD)] 36.7 (9.7) 38.1 (9.0) 0.634a

Gender [n (%)]MaleFemale 20 (90.9%)2 (9.1%) 19 (86.4%)3 (13.6%) 0.644b
Disease duration [years; mean (SD)] 9.1 (4.7) 11.0 (4.4) 0.198a
Family history, [yes (%)] 4 (18.2%) 3 (13.6%) 0.689b
Marital status [n (%)]SingleMarriedDivorced 12 (54.5%)9 (40.9%)1 (4.5%) 8 (36.4%)12 (54.5%)2 (9.1%) 0.227b
Education [n (%)]SecondaryDiplomaHigher education 1 (4.5%)16 (72.7%)5 (22%) 1 (4.5%)18 (81.8%)3 (13.6%) 0.520b
Type of ADHD [n (%)]InattentiveHyperactiveCombined 1 (4.5%)1 (4.5%)20 (90.9%) 1 (4.5%)1 (4.5%)20 (90.9%) 1.000b
Smoking, [yes (%)] 18 (81.8%) 16 (72.7%) 0.721b
History of substance abuse, [yes (%)] 4 (18.2%) 4 (18.2%) 1.000b
Baseline ASRS score [ mean (SD)] 51.8 (8.3) 50.8 (7.9) 0.673a
Baseline CAARS score [ mean (SD)] 42.3 (7.7) 40.7 (8.8) 0.529a

P-value of < 0.05 was considered statistically significant.

SD: standard deviation
a
Student T-test.
b
Chi-square test.

baseline to the study endpoint (df=1.584, F=3.939, and P-

value=0.033) (Fig. 2b). However, there was no significant difference
in the improvement of CAARS scores between saffron and placebo
from baseline to week 3 or 6 (P-value=0.564 and 0.089, respectively).
Moreover, there was no significant between-group difference re­
garding CAARS scores in baseline, week 3, and week 6 (P-
value=0.529, 0.250, and 0.249). Finally, our findings showed that
treatment with Ritalin in both saffron and placebo groups leads to
significant improvement in CAARS scores in ADHD patients
(df=1.584, F=162.317, and P-value < 0.001).

3.4. Adverse effects

Seven side effects with mild to moderate severity were observed

in patients (Table 3). The most common side effect was insomnia in
both groups. Fisher's exact test showed no significant difference
regarding the frequency of the adverse effects between the saffron
and placebo groups. No unforeseen sign or symptom was reported
by the trial participants, and no serious adverse event/death oc­
curred.

4. Discussion

To the best of our knowledge, this is the first randomized,

Fig. 2. Scores of a) ASRS and b) CAARS in saffron and placebo groups.
(P-value=0.024), but not in baseline and week 3 (P-value=0.673 and
0.627, respectively). Finally, our findings showed that treatment with
Ritalin in both saffron and placebo groups leads to significant im­
provement in ASRS scores in ADHD patients (df=2, F=172.584, and P-
value < 0.001) Table 2.
3.3. CAARS scores
The results from GLM repeated-measure analysis demonstrated a
significant time × treatment interaction effect for CAARS score from
double-blinded clinical trial investigating the beneficial effects of
saffron as an adjunctive treatment in adults with ADHD. The present
randomized, double-blind, placebo-controlled clinical trial demon­
strated that six weeks of adjuvant therapy with saffron and Ritalin
improved ADHD symptoms in adults. Overall, our findings demon­
strated that saffron adjunctive treatment led to greater improve­
ment in ASRS and CAARS, i.e. primary outcome measures the study,
compared to placebo. Additionally, no significant difference was
seen between the saffron and the placebo group in terms of adverse
effects. Given all the aforementioned data, saffron can be considered
an effective and safe option in the management of ADHD.
ADHD symptoms are mainly due to an imbalance of dopami­
nergic and noradrenergic systems in the CNS areas like caudate and
cerebellum [7,39]. Therefore, methylphenidate or amphetamine,
which has been shown to enhance dopamine and norepinephrine in
the above areas, plays a promising role in ameliorating ADHD
symptoms [39–43]. Ritalin and other stimulants are associated with
adverse events, such as decreased appetite, insomnia, headache,
increased blood pressure, weight loss, dizziness and nausea. Thus, a
lower number of patients are inclined to use stimulants. Further­
more, due to no response to stimulants in 30% of patients, extensive
studies are underway to find alternative or adjuvant chemical and
herbal drugs. Among non-stimulant drugs, antidepressants have
often been used as an effective alternative treatment in clinical trials

40
B. Pazoki, N. Zandi, Z. Assaf et al. Advances in Integrative Medicine 9 (2022) 37–43

Table 2
Comparison of ASRS and CAARS scores between the two trial groups.

Saffron group (n = 22) Placebo group (n = 22) Mean difference (95% CI) P-valuea

ASRS Baseline 51.86 (8.36) 50.81 (7.95) 1.04 (−3.92 to 6.01) 0.673
Week 3 40.81 (8.08) 42.00 (7.92) -1.18 (−6.05 to 3.69) 0.627
Week 6 30.72 (6.03) 34.90 (5.84) -4.18 (−7.79 to −0.56) 0.024
Change from baseline to Week 3 11.04 (6.78) 8.81 (6.39) 2.22 (−1.78 to 6.23) 0.269
Change from baseline to Week 6 21.13 (7.36) 15.90 (7.47) 5.22 (0.71–9.74) 0.024
CAARS Baseline 42.36 (7.77) 40.77 (8.81) 1.59 (−3.46 to 6.64) 0.529
Week 3 33.45 (7.62) 30.90 (6.80) 2.54 (−1.85 to 6.94) 0.250
Week 6 23.13 (7.29) 25.63 (6.88) -2.50 (−6.81 to 1.81) 0.249
Change from baseline to Week 3 8.90 (5.97) 9.86 (4.85) -0.95 (−4.26 to 2.35) 0.564
Change from baseline to Week 6 19.22 (8.24) 15.13 (7.30) 4.09 (−0.64 to 8.83) 0.089

CI: Confidence Interval

P-value of < 0.05 was considered statistically significant
Data are shown as mean (standard deviation).
Adult ADHD Self‐Report Scale: ASRS
Adult ADHD Rating Scales-self report: screening version: CAARS-RS
a
Independent T-test

Table 3 children. We provided a placebo group in our study to indicate a

The frequency of adverse events in the study populations. more accurate assessment and, to the best of our knowledge, this is
Side effect Saffron group Placebo group P-values the first clinical trial of saffron efficacy as adjuvant therapy to Ritalin
(n = 28) (n = 28) on adults with ADHD.
Insomnia 17 (77.3%) 18 (81.8%) 1.000 Our study is not without limitations. The small sample size might
Headache 14 (63.6%) 15 (68.2%) 1.000 limit the generalizability of our findings, and thus larger multi-
Abdominal pain 13 (59.1%) 11 (50.0%) 0.763 center clinical studies are required to confirm these results before
Decreased appetite 16 (72.7%) 14 (63.6%) 0.747
any recommendation for broad clinical use of saffron. The period of
Nausea 3 (13.6%) 5 (22.7%) 0.698
Itching 4 (18.2%) 3 (13.6%) 1.000 our trial was relatively short (six weeks). The short time span of this
Cough 2 (9.1%) 3 (13.6%) 1.000 study might not reveal the long-term therapeutic and adverse effects
P-value of < 0.05 was considered statistically significant.
of saffron.
*Fisher's Exact test was used for comparison of all adverse events.

5. Conclusion
[13,32,44]. One of the effective antidepressant drugs for ADHD is
Around 30% of patients with ADHD do not respond to Ritalin or
Bupropion which has been evaluated in a 6-week trial on 38 patients
cannot tolerate its side effects, necessitating the consideration of
diagnosed with ADHD which showed comparable safety and efficacy
alternative options. In this randomized, double-blind, placebo-con­
compared to Ritalin in children and adults [17,18]. Also, another
trolled clinical trial, we demonstrated that saffron combination
randomized clinical trial examined the efficacy of Agomelatine in
therapy with Ritalin can effectively improve symptoms of patients
comparison with Ritalin on 6–15-year-old children with ADHD over
with ADHD. However, the outcomes of this study must be con­
6 weeks which showed no significant difference in results of Parent
sidered preliminary and further studies with larger sample sizes and
and Teacher ADHD-RS-IV scores between two groups at the end of
longer follow-up are needed to confirm our findings.
the study [16].
What is already known about the topic:
Saffron is a traditional herbal medicine with documented ther­
apeutic effects in the treatment of depression, seizures, inflamma­
1. ADHD is a mental-behavioral disorder affecting both children and
tion, sexual dysfunction and learning and memory deficits [45–47].
adults.
It has been suggested that saffron and its main constituents, in­
2. The beneficial effects of Crocus sativus (saffron) are documented
cluding crocin, picrocrocin, and safranal crocetin, have neuropro­
in children with ADHD.
tective effects [24]. They play a role through the inhibition of
3. The potential effect of saffron on CNS disorders may be through
norepinephrine and dopamine reuptake, being GABA-α agonist and
dopamine and norepinephrine systems.
NMDA receptor antagonist [35,48]. Regarding saffron potentials,
recent studies have focused on the role of saffron and its compo­
What this paper adds:
nents in animal studies and clinical trials to figure out a new drug for
neurobehavioral disorders with lower side effects. Saffron has also
1. Saffron might be beneficial in adults with ADHD.
shown antidepressant effects in recent studies which revealed equal
2. Saffron may increase the efficacy of Ritalin in the treatment of
efficacy compared to imipramine and fluoxetine [19,27–30]. Favor­
ADHD patients.
able effects of saffron on monoaminergic and glutaminergic systems
3. Saffron is a safe treatment for ADHD.
can lead to an improvement in the treatment of ADHD individuals
[34,35]. In an animal study on adult male Wistar rats, pretreatment
with safranal decreased the locomotor hyperactivity, stereotypic Ethical Statement
behavioral and ataxia induced by single systemic injection of MK-
801 [49]. Additionally, pretreatment with saffron extract sig­ This study was approved by the institutional review board (IRB)
nificantly ameliorated morphine-induced hyperactivity in female and the ethics committee of Tehran University of Medical Sciences
mice [50]. Saffron has been assessed for the treatment of ADHD (IR.TUMS.VCR.REC.1397.259). Also, this study was in accordance with
symptoms in children. In a six-week study on patients aged 6–17 the Declaration of Helsinki and its subsequent revision. All patients
years old who were diagnosed with ADHD, saffron demonstrated the provided written informed consent, being aware of the procedure
same efficacy in comparison with Ritalin [33]. However, the study and purpose of the study and the possibility of leaving the trial and
did not have a placebo-controlled group and was restricted to returning to their standard treatment without any problem

41
B. Pazoki, N. Zandi, Z. Assaf et al.
concerning their relationship with their physician. Clinical ex­
aminations of patients were conducted on four separate sessions:
baseline, week 3, and week 6. This trial is registered at the Iranian
registry of clinical trials (www.irct.ir; registration number:
IRCT20090117001556N111).
Funding
This study was supported by a grant from Tehran University of
Medical Sciences to Prof. Shahin Akhondzadeh (Grant No: 38140).
CRediT authorship contribution statement
Benyamin Pazoki, Nadia Zandi, Zeinab Assaf, Hossein Sanjari
Moghaddam, Arefeh Zeinoddini participated in data acquisition
analysis and preparation of the first draft of manuscript. Shahin
Akhondzadeh and Mohammadreza Mohammadi designed the
manuscript, provided the outlines for presentation of the study,
supervised the study process and edited the final manuscript. All
authors have reviewed the process of data analysis, commented on
previous versions of the manuscript, and approved the final article.
Acknowledgements
This randomized clinical trial was Dr. Zeinab Assaf’s postgraduate
thesis toward the Iranian Board of Psychiatry.
Declarations of interest
None.
Appendix A. Supporting information
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.aimed.2022.01.002.
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