https://doi.org/10.5812/ijpbs.108390

A Comparison of Methylphenidate (MPH) and Combined Methylphenidate with Crocus sativus (Saffron) in the Treatment of Children and Adolescents with ADHD: A Randomized, Double-Blind, Parallel-Group, Clinical Trial

authors:

avatar Mojtaba Khaksarian 1 , avatar Nazanin Ahangari 2 , avatar Abbas Masjedi-Arani ORCID 2 , avatar Iman Mirr 3 , avatar Hassan Jafari 4 , avatar Saeed Kordian 5 , avatar Roghieh Nooripour 6 , avatar Saba Hassanvandi ORCID 7 , *

Department of Physiology, School of Medicine, Lorestan University Medical Sciences, Khorramabad, Iran
Department of Clinical Psychology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Department of Medicine, Lorestan University Medical Sciences, Khorramabad, Iran
Educational Administration, Farhangian University, Tehran, Iran
Psychiatry Department, Lorestan University Medical Sciences, Khorramabad, Iran
Ph.D of Counseling, Department of Counseling, Faculty of Education and Psychology, Alzahra University, Tehran, Iran
Ph.D of Educational Psychology, Department of Educational Psychology, Faculty of Education and Psychology, Alzahra University, Tehran, Iran
Iranian Journal of Psychiatry and Behavioral Sciences: Vol.15, issue 3; e108390
published online: July 31, 2021
article type: Research Article
received: August 19, 2020
revised: April 24, 2021
accepted: May 15, 2021

How To Cite Khaksarian M, Ahangari N, Masjedi-Arani A, Mirr I, Jafari H, et al. A Comparison of Methylphenidate (MPH) and Combined Methylphenidate with Crocus sativus (Saffron) in the Treatment of Children and Adolescents with ADHD: A Randomized, Double-Blind, Parallel-Group, Clinical Trial. Iran J Psychiatry Behav Sci. 2021;15(3):e108390. https://doi.org/10.5812/ijpbs.108390.

Abstract

Background:

Attention-deficit/hyperactivity disorder (ADHD) is characterized by behavioral and neurodevelopmental problems. It is estimated that 3 - 7% of children and adolescents suffer from this problem. Apart from synthetic drugs, other effective types of medication like herbal medicines are of great importance.

Objectives:

This study aimed to evaluate the effectiveness of methylphenidate (MPH) and its combination with Crocus sativus (saffron) in the treatment of children suffering from ADHD.

Methods:

The sample included 70 children aged between 6 and 16 years who had been diagnosed with ADHD. The patients were randomly assigned into two equal groups (n = 35 in each group). While both groups received 20 or 30 mg/d of MPH (20 and 30 mg/d for < 30 and > 30, respectively), one of them also received 20 or 30 mg/d of saffron in a capsule based on BMI (20 and 30 mg/d for < 30 and > 30, respectively). To collect data, parents and teachers completed Attention-Deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV). Also, for analyzing the data, the repeated measures analysis of variance (RMANOVA) was used.

Results:

The results of general linear model (GLM) repeated measures indicated that in both groups, the patients had less symptoms after eight weeks of treatment. However, after four weeks, the average score assigned by the parents and teachers in the MPH with saffron group was lower than the average total score in the MPH group (P < 0.05).

Conclusions:

Using MPH combined with saffron proved to be more effective in the treatment of patients suffering from ADHD compared to separate treatments. It seems that the duration of therapy can be reduced and the effectiveness be improved by prescribing proposed combined treatment.

1. Background

Attention deficit/hyperactivity disorder (ADHD), with a prevalence of 3 - 7%, is one of the most important psychiatric disorders in children (1). The distinguished features of this disorder include such symptoms as inattention, hyperactivity, and impulsivity that do not match with the age of child development (2). There are different approaches to manage ADHD, such as psychotherapy and pharmacotherapy, and the latter one is the standard approach for the reduction of different symptoms of ADHD. Among psychiatric drugs, methylphenidate (MPH) is the most common and safest medication for treating ADHD, so that different studies have used it for treating the related symptoms (3, 4). MPH reduces cognitive deficits through a dopaminergic effect (5). However, about 30% of affected children and adolescents do not respond to MPH (6). So, in recent years, alternative treatments have been considered. Herbal remedies have been considered throughout the history. It is noteworthy that herbal medicines have been widely used worldwide (7). Accordingly, around 80% of people in different parts of the world accept these remedies as effective drugs (8). In the treatment of depression, herbal medicines with important properties such as low risk and milder side effects are considered as alternative treatment options (9-12). In this regard, one of the herbal medicines is Crocus sativus (saffron), which has extraordinary properties such as anti-cancer and anti-platelet effects, antioxidant benefits, and anti-inflammatory medical usage (9). The underlying hypothesis of the effect of saffron on ADHD symptoms is based on psychiatric and clinical evidence that reinforces the hypothesis of dopamine. In other words, saffron increases dopamine by increasing activity and brain waves and plays the role of stimulants (13). Besides, it has antispasmodic, antiseptic, antidepressant, and anticonvulsant therapeutic applications (14). Accordingly, it is believed that this expensive spice can inhibit the reuptake of dopamine and norepinephrine. Noticeably, dopamine and norepinephrine are N-methyl D-aspartic acid (NMDA) receptor antagonists and also GABAA agonists (15, 16).

Scientifically, different studies have demonstrated efficacy of this expensive spice by exact clinical trials. These studies showed that saffron was capable of enhancing memory function and reducing depression symptoms and anxiety (17, 18). Others evaluated the efficacy of MPH and saffron in treating children with ADHD. Their results showed no significant difference between the two groups under treatment with MPH and saffron (19). Some research also evaluated the effectiveness of other herbal medicine such as Valerian root, the results of which were significant (20).

2. Objectives

Since individuals with ADHD have increased rates of other psychiatric disorders such as alcohol-related disorders, drug addiction, divorce, family conflicts, and deadly accidents in adulthood (21), we hypothesized that combining saffron with MPH would have higher efficacy than MPH alone. It was assumed that this herbal supplement would be able to improve the effectiveness of treatment. Given these studies and the lack of comparative research in this field, the authors of this article conducted a comparative study to evaluate MPH and its combined use with saffron among children and adolescents suffering from ADHD.

3. Methods

3.1. Procedure and Study Setting

The present clinical trial was a randomized, double-blind, parallel-group study conducted over an 8-week period (from February 2020 to April 2020) in Mehr Psychiatric Hospital affiliated to Lorestan University of Medical Sciences (LUMS), Iran. The ethics committee of LUMS approved all study protocols (IR.LUMS.REC.1398.227), and the study was registered in Iranian Registry of Clinical Trials (IRCT20190602043790N2). The study was conducted according to the principles of the Declaration of Helsinki. Patients' symptoms were measured at the baseline time and weeks four and eight. To meet the ethical codes, all the steps and study objectives were described to the children. Adolescents and their parents. Written informed consent was obtained from the children and adolescents or their parents. Moreover, all necessary explanations concerning the right to withdraw from the study for any reason were provided to the participants and their parents.

3.2. Sample Size

Through calculating the mean difference (MD = 3) and standard deviation (SD = 3) in the pilot study of ADHD-RS-IV (Attention-Deficit/Hyperactivity Disorder Rating Scale-IV) and regarding the statistical power of 80% (P < 0.05), 32 patients were needed for each group (n = 64). Considering 10% attrition rate, the statistics specialist proposed 35 patients to be included in each group (n = 70).

3.3. Participants

Recruitment process was performed among patients of both sexes aged 6 - 16 years admitted to the outpatient wards. All patients met the necessary criteria for ADHD diagnosis according to DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition). All the eligible patients had total and/or subscale scores on ADHD-RS-IV and at least SD = 1.5 from the norms (23). Before any intervention, the child psychiatrist diagnosed ADHD based on the DSM-5 criteria for all participants and took a complete medical history. A simple randomization method was used, and the unit of randomization was individual. Using the table of random numbers, patients were randomly divided into two groups: MPH or a combination of MPH and saffron. Even numbers were considered for the MPH group and odd numbers for the MPH and saffron group. Random allocation was done by the researcher; the clinical caregiver and data analyzer were not aware of the allocation of patients.

Exclusion criteria included psychiatric comorbidities (except for oppositional defiant disorder), seizure, cardiac disease, using any external matter that might interfere with saffron, history of allergy to saffron, and a systolic blood pressure (SBP) over 125 mm Hg. The physiological examinations included body mass index (BMI), pulse rate, and blood pressure.

3.4. Interventions

The samples were randomly assigned into two parallel groups. The first group only received MPH at the dose of 0.3 - 1 mg/d. According to the protocol, MPH was prescribed during the trial at the below doses: 10 mg/d (5 mg for morning and midday equally) in week 1; 20 mg/d (10 mg for morning and midday equally) in week 2; and 20 mg/d (for < 30 kg and 30 mg/d for > 30 kg; 10 mg for morning, midday, and evening equally) in week 3 and thereafter. The MPH plus saffron group received previous prescription with saffron capsules at a dose of 20 - 30 mg/d according to the BMI (20 and 30 mg/d for < 30 and > 30 kg, respectively).

3.5. Instrument

Parent and teacher ratings of ADHD-RS-IV was used for evaluating behavioral changes in patients. This tool provided valid measurement of attention and behavioral problems in children and adolescents with ADHD over the past six months and took about five minutes to be completed (22, 23). This instrument is consistent with the DSM-V criteria for diagnosis of ADHD (24). In this tool, 18 distinctive symptoms of ADHD are assessed by a 4-point Likert scale. Psychometric characteristics of this measure were confirmed (23). In this questionnaire, parents and teachers are asked to choose one of the options (frequency of behavior). The first nine items are related to inattention symptoms, and the second nine items are related to hyperactivity and impulsivity symptoms. Cronbach's alpha was calculated at 0.90 for the school and home versions (24). Furthermore, construct validity of the combined subscale for the two groups of respondents was reported as 60 and 65% for parents and teachers, respectively (24).

3.6. Safety

All participants were free to withdraw from the trial at any stage. Also, sufficient information was provided to inform the members of the research team in case of any unexpected side effects. Throughout the trial, side effects were exactly investigated using a checklist; 25 side effects, including neurological and psychological ones, as well as other types were recorded (25). Over the course of eight weeks, there was no dropout due to different side effects.

3.7. Data Analysis

For data analysis, the IBM SPSS Statistics (version 21) (IBM Corporation, Armonk, NY) was used. Number of patients and percentages were considered as categorical variables and mean, and SD were counted as continuous variables. To compare the trend of changes in ADHD Rating Scale scores during eight weeks of treatment, the general linear model (GLM) repeated measures was used. Between-subject and within-subject factors were counted for study groups and times of measurements, respectively. Greenhouse–Geisser correction was performed for reporting the degrees of freedom (DF) if Mauchly’s test of sphericity was statistically significant. Moreover, for evaluating effectiveness of each protocol in reducing ADHD symptoms, one-way analysis of variance (ANOVA) was performed. T-test was also used to compare changing the status of scores from baseline in both groups. Two statistical methods, including Fisher’s exact test and chi-square test, were also used for comparing the categorical variables. Also, in all stages of analysis, a P-value < 0.05 was considered as the significant level.

4. Results

In this study, out of a total of 90 children and adolescents aged 6 - 16 years, 12 patients were excluded due to not meeting the inclusion criteria. In this way, 39 patients were randomly assigned to MPH group and 39 to the MPH plus saffron group. In weeks 3 - 4, eight subjects refused to participate in the trial. Thus, in every group, 35 patients finished the trial (Figure 1). Also, there was no significant difference between the two groups in terms of baseline characteristics such as age (Table 1).

Flow diagram of the trial
Flow diagram of the trial
Figure 1.

Flow diagram of the trial

Table 1.

Baseline Characteristics of the Two Study Groups

VariablesNMeanSDP-Value
Age0.435
MPH3511.032.31
MPH & Saffron3510.572.56
Parent inattention baseline0.261
MPH3519.132.98
MPH & Saffron3519.993.33
Parent hyperactivity baseline0.824
MPH3520.113.16
MPH & Saffron3519.933.47
Teacher inattention baseline0.793
MPH3518.513.00
MPH & Saffron3518.713.20
Teacher hyperactivity baseline0.602
MPH3518.392.65
MPH & Saffron3518.773.38
Parent total baseline0.618
MPH3539.275.23
MPH & Saffron3539.956.07
Teacher total baseline0.661
MPH3536.944.82
MPH & Saffron3537.526.07

4.1. Parent ADHD-RS-IV

As the results indicated, in baseline stage, no significant difference was observed between the two study groups in parent ADHD Rating Scale scores (39.27 ± 5.23 for MPH and 36.94 ± 4.82 for MPH plus saffron group, df = 68, P < 0.05). The groups also proved to be different according to the results of GLM. Moreover, the effect of interaction between time and treatment was similar across time (Figure 2). In each group, the trend of the effect of time × treatment interaction was similar. Regarding the subscales of hyperactivity and inattention, Greenhouse-Geisser corrected GLM repeated measures indicated no change in between-subject groups. This report was similar for the two subscales. Therefore, the trend analysis in the fourth and eighth weeks showed significant differences in the scores of parent ADHD Rating Scale among the two groups (P < 0.05). Also, post hoc comparisons showed a significant reduction in Parent ADHD scores in the fourth and eighth weeks in both groups (P < 0.05). After four weeks of treatment, the patients achieved the desired result. The average score of parents in the MPH with saffron group was lower than the average total score of the parents in the MPH group after eight weeks (P < 0.05) (Table 1).

The GLM repeated measures for investigating MPH versus MPH with saffron treatments on parent ADHD Rating Scale Score
The GLM repeated measures for investigating MPH versus MPH with saffron treatments on parent ADHD Rating Scale Score
Figure 2.

The GLM repeated measures for investigating MPH versus MPH with saffron treatments on parent ADHD Rating Scale Score

4.2. Teacher ADHD-RS-IV

As the results indicated, in baseline stage, no significant difference was observed between the two study groups in teacher ADHD Rating Scale scores (36.94 ± 4.82 and 37.52 ± 6.07 for MPH and MPH plus saffron group, respectively) (df = 68, P < 0.05). According to the results of GLM repeated measures, there was no change in between-subject groups. Moreover, effect of time × treatment interaction was similar across time (Figure 3). In each group, the trend of the effect of time × treatment interaction was similar for two subscales, including hyperactivity and inattention. Accordingly, MPH improved ADHD symptoms, but MPH plus saffron had excellent effect on the reduction of symptoms. This report was similar for two subscales. There was a significant difference between the two groups in the scores of teacher ADHD Rating Scale at the fourth and eighth weeks. In other words, the difference between the two groups after four weeks was obtained in the mean scores of hyperactivity, inattention, and total score. Post hoc comparisons showed significant reductions in Teacher ADHD scores at weeks 4 and 8 between the two groups (P < 0.05). Accordingly, the difference between baseline characteristics in weeks 4 and 8 was significant among the two groups (P < 0.05). After four weeks of treatment, patients achieved the desired result (Table 2).

The GLM repeated measures for investigating MPH versus MPH with saffron treatments on teacher ADHD Rating Scale Score
The GLM repeated measures for investigating MPH versus MPH with saffron treatments on teacher ADHD Rating Scale Score
Figure 3.

The GLM repeated measures for investigating MPH versus MPH with saffron treatments on teacher ADHD Rating Scale Score

Table 2.

Attention-Deficit/Hyperactivity Disorder Rating Scale-IV Scores (Parents and Teachers) a

VariablesMPHMPH & SaffronP-Value
Parent inattention week 417.69 ± 3.2413.54 ± 3.460.000
Parent inattention week 813.77 ± 4.79.21 ± 3.710.000
Parent hyperactivity week 417.18 ± 3.9213.72 ± 3.430.000
Parent hyperactivity week 813.37 ± 5.169.83 ± 3.510.001
Parent total week 434.88 ± 6.627.28 ± 6.060.000
Parent total week 827.15 ± 9.4619.07 ± 6.90.000
Teacher inattention week 417.91 ± 2.9213.4 ± 2.720.000
Teacher inattention week 813.49 ± 5.719.19 ± 4.030.001
Teacher hyperactivity week 417.41 ± 3.7313.75 ± 2.380.000
Teacher hyperactivity week 814.03 ± 5.768.69 ± 3.730.000
Teacher total week 435.36 ± 6.227.2 ± 4.490.000
Teacher total week 827.56 ± 11.2617.93 ± 7.460.000

a Values are expressed as mean ± SD.

4.3. Side Effects

No serious side effects were reported during the study, and all observed side effects were mild to moderate. Furthermore, there was no significant difference between patients in MPH and MPH plus saffron groups in terms of repetition of side effects.

5. Discussion

The results of this study supported the efficacy of the combination of MPH and C. sativus (saffron) over MPH alone in the treatment of patients suffering from ADHD. The results of GLM also showed that combined MPH with C. sativus (saffron) was more effective than MPH alone after 4 - 8 weeks of treatment. Moreover, after four weeks, the effectiveness of treatment was obvious. So, the novelty of this trial was that by prescribing MPH with saffron, the duration of treatment was reduced to four weeks. This reduction in time can be effective in accelerating the treatment process and reducing side effects.

ADHD is widely recognized as a common childhood neurodevelopmental psychiatric disorder, and pharmacological approach is the most accepted approach for its treatment. The Food and Drug Administration (FDA) approved some stimulant drugs like Ritalin, methylin ER, cotempla XR, and metadate CD to treat ADHD; these first-line drugs are the most prestigious remedies. However, for psychiatrists, the foremost drugs are ritalin and dexmethylphenidate, respectively (26). Brain imaging studies have shown that dopamine and norepinephrine pathways are involved in the pathology of ADHD. Dopamine and norepinephrine pathways are also involved in other comorbid disorders such as depression, anxiety, and panic (27-33). Therefore, it is not surprising that by regulating these pathways some improvements occur in mood and concentration of ADHD patients; they also show why MPH is effective for the treatment of ADHD (34). Taken together, the first-line treatment for ADHD fails in up to 20 - 30% of patients suffering from ADHD (35).

This randomized study showed that saffron, as an herbal medicine, could be an effective complementary treatment for ADHD like other disorders such as cancer and metabolic syndromes (36). Saffron possesses antidepressant and anti-inflammatory properties and also has a radical scavenging capability (10). Moreover, some studies have been indicative of its anti-Alzheimer, anti-schizophrenia, and anti-Parkinson properties (37-41).

Considering herbal approach to the treatment of ADHD, studies have shown that saffron is an antidepressant supplement, and it has many marvelous effects in relieving ADHD obvious symptoms. Saffron reduces the symptoms of abnormalities and acts as a safe drug by regulating neurotransmitters and modulating their secretion (10, 22, 42-44). Moreover, saffron has also been shown to exert antidepressant effects in clinical trials. Thus, we hypothesized that saffron could be beneficial in combination with MPH and alleviate symptoms effectively. Similarly, the monoaminergic and glutamatergic systems of saffron (45) supported by rich literature make this plant a complementary medicine capable of treating ADHD.

From a biological standpoint, one of the explanations for the high effectiveness of saffron in combination with MPH is its effect on monoaminergic and glutamatergic systems. Chemical compounds of saffron can improve mood and modulate brain function through monoaminergic and glutamatergic systems (45-48). Furthermore, due to the pathophysiology of ADHD and the involvement of various mechanisms, such as reduced and fluctuated brain volume in some brain areas (prefrontal cortex, cerebellum, and basal ganglia), it seems that these regions are directly involved in ADHD emergence (49). Some researchers believe that saffron can increase the power of neuronal plasticity and neurogenesis or growth of neural tissue of specific brain regions, such as hippocampus, nucleus accumbens, and prefrontal cortex. In fact, neuronal plasticity by increasing brain activity and regulating waves can be effective in keeping the brain of people with ADHD self-regulated. This ability of the brain is also effective in regulating the emotions of sufferers (9). It is noteworthy that combined treatment showed its effectiveness in a shorter period of time compared to MPH treatment alone. So, saffron has a golden effect on shortening the duration of treatment to four weeks, and it has fewer side effects for children and adolescents due to its herbal properties.

This clinical trial had some useful results. A randomized method and a double-blind design were among its advantages. Nonetheless, there were some limitations, that is, lack of a placebo-controlled trial and lack of a follow-up period. These limitations should be addressed in future trials. As a result, future randomized placebo-controlled trials are recommended to evaluate patients during the process of treatment more rigorously.

5.1. Conclusions

In this study, although MPH reduced ADHD symptoms, the combination of MPH and saffron proved to be more effective than MPH alone. In addition, by prescribing combined treatment, the duration of treatment can be reduced to four weeks. Considering the positive effect of saffron, future studies should consider its use for a broader spectrum of psychiatric disorders like anxiety disorders, depression, etc.

References

  • 1.

    Castells X, Ramos-Quiroga JA, Bosch R, Nogueira M, Casas M. Amphetamines for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane Database Syst Rev. 2011;(6). CD007813. [PubMed ID: 21678370]. https://doi.org/10.1002/14651858.CD007813.pub2.

  • 2.

    American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-5. Washington, USA: American Psychiatric Association; 2013.

  • 3.

    Childress AC, Stark JG. Diagnosis and treatment of attention-deficit/hyperactivity disorder in preschool-aged children. J Child Adolesc Psychopharmacol. 2018;28(9):606-14. [PubMed ID: 30388032]. https://doi.org/10.1089/cap.2018.0057.

  • 4.

    Winters DE, Fukui S, Leibenluft E, Hulvershorn LA. Improvements in irritability with open-label methylphenidate treatment in youth with comorbid attention deficit/hyperactivity disorder and disruptive mood dysregulation disorder. J Child Adolesc Psychopharmacol. 2018;28(5):298-305. [PubMed ID: 29708762]. [PubMed Central ID: PMC6016730]. https://doi.org/10.1089/cap.2017.0124.

  • 5.

    Storebo OJ, Krogh HB, Ramstad E, Moreira-Maia CR, Holmskov M, Skoog M, et al. Methylphenidate for attention-deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta-analyses and trial sequential analyses of randomised clinical trials. BMJ. 2015;351:h5203. [PubMed ID: 26608309]. [PubMed Central ID: PMC4659414]. https://doi.org/10.1136/bmj.h5203.

  • 6.

    Spencer T, Biederman J, Wilens T, Harding M, O'Donnell D, Griffin S. Pharmacotherapy of attention-deficit hyperactivity disorder across the life cycle. J Am Acad Child Adolesc Psychiatry. 1996;35(4):409-32. [PubMed ID: 8919704]. https://doi.org/10.1097/00004583-199604000-00008.

  • 7.

    Ramulondi M, de Wet H, van Vuuren S. Toxicology of medicinal plants and combinations used in rural northern KwaZulu-Natal (South Africa) for the treatment of hypertension. J Herb Med. 2019;16:100251. https://doi.org/10.1016/j.hermed.2018.12.001.

  • 8.

    Enogieru AB, Omoruyi SI, Hiss DC, Ekpo OE. GRP78/BIP/HSPA5 as a therapeutic target in models of Parkinson's disease: A mini review. Adv Pharmacol Sci. 2019;2019:2706783. [PubMed ID: 30949202]. [PubMed Central ID: PMC6425347]. https://doi.org/10.1155/2019/2706783.

  • 9.

    Khaksarian M, Behzadifar M, Behzadifar M, Alipour M, Jahanpanah F, Re TS, et al. The efficacy of Crocus sativus (saffron) versus placebo and fluoxetine in treating depression: A systematic review and meta-analysis. Psychol Res Behav Manag. 2019;12:297-305. [PubMed ID: 31118846]. [PubMed Central ID: PMC6503633]. https://doi.org/10.2147/PRBM.S199343.

  • 10.

    Moshiri M, Vahabzadeh M, Hosseinzadeh H. Clinical applications of saffron (Crocus sativus) and its constituents: A review. Drug Res (Stuttg). 2015;65(6):287-95. [PubMed ID: 24848002]. https://doi.org/10.1055/s-0034-1375681.

  • 11.

    Hosseini A, Razavi BM, Hosseinzadeh H. Pharmacokinetic properties of saffron and its active components. Eur J Drug Metab Pharmacokinet. 2018;43(4):383-90. [PubMed ID: 29134501]. https://doi.org/10.1007/s13318-017-0449-3.

  • 12.

    Samarghandian S, Farkhondeh T. Saffron and neurological disorders. Saffron: The age-old panacea in a new light. Massachusetts, United States: Academic Press; 2020. p. 103-16.

  • 13.

    Shamsa A, Hosseinzadeh H, Molaei M, Shakeri MT, Rajabi O. Evaluation of Crocus sativus L. (saffron) on male erectile dysfunction: a pilot study. Phytomedicine. 2009;16(8):690-3. [PubMed ID: 19427775]. https://doi.org/10.1016/j.phymed.2009.03.008.

  • 14.

    Srivastava R, Ahmed H, Dixit RK, Saraf SA; Dharamveer. Crocus sativus L.: A comprehensive review. Pharmacogn Rev. 2010;4(8):200-8. [PubMed ID: 22228962]. [PubMed Central ID: PMC3249922]. https://doi.org/10.4103/0973-7847.70919.

  • 15.

    Tamaddonfard E, Hamzeh Gooshchi N, Seiednejad-Yamchi S. Central effect of crocin on penicillin-induced epileptiform activity in rats. Pharmacol Rep. 2012;64(1):94-101. [PubMed ID: 22580525]. https://doi.org/10.1016/s1734-1140(12)70735-1.

  • 16.

    Kalueff AV, Nutt DJ. Role of GABA in anxiety and depression. Depress Anxiety. 2007;24(7):495-517. [PubMed ID: 17117412]. https://doi.org/10.1002/da.20262.

  • 17.

    Wang Y, Han T, Zhu Y, Zheng CJ, Ming QL, Rahman K, et al. Antidepressant properties of bioactive fractions from the extract of Crocus sativus L. J Nat Med. 2010;64(1):24-30. [PubMed ID: 19787421]. https://doi.org/10.1007/s11418-009-0360-6.

  • 18.

    Akhondzadeh S, Shafiee Sabet M, Harirchian MH, Togha M, Cheraghmakani H, Razeghi S, et al. A 22-week, multicenter, randomized, double-blind controlled trial of Crocus sativus in the treatment of mild-to-moderate Alzheimer's disease. Psychopharmacology (Berl). 2010;207(4):637-43. [PubMed ID: 19838862]. https://doi.org/10.1007/s00213-009-1706-1.

  • 19.

    Baziar S, Aqamolaei A, Khadem E, Mortazavi SH, Naderi S, Sahebolzamani E, et al. Crocus sativus L. Versus methylphenidate in treatment of children with attention-deficit/hyperactivity disorder: A randomized, double-blind pilot study. J Child Adolesc Psychopharmacol. 2019;29(3):205-12. [PubMed ID: 30741567]. https://doi.org/10.1089/cap.2018.0146.

  • 20.

    Gromball J, Beschorner F, Wantzen C, Paulsen U, Burkart M. Hyperactivity, concentration difficulties and impulsiveness improve during seven weeks' treatment with valerian root and lemon balm extracts in primary school children. Phytomedicine. 2014;21(8-9):1098-103. [PubMed ID: 24837472]. https://doi.org/10.1016/j.phymed.2014.04.004.

  • 21.

    Biederman J, Faraone SV, Spencer TJ, Mick E, Monuteaux MC, Aleardi M. Functional impairments in adults with self-reports of diagnosed ADHD: A controlled study of 1001 adults in the community. J Clin Psychiatry. 2006;67(4):524-40. [PubMed ID: 16669717]. https://doi.org/10.4088/jcp.v67n0403.

  • 22.

    Salardini E, Zeinoddini A, Kohi A, Mohammadi MR, Mohammadinejad P, Khiabany M, et al. Agomelatine as a treatment for attention-deficit/hyperactivity disorder in children and adolescents: A double-blind, randomized clinical trial. J Child Adolesc Psychopharmacol. 2016;26(6):513-9. [PubMed ID: 27286139]. https://doi.org/10.1089/cap.2016.0024.

  • 23.

    Abbasi SH, Heidari S, Mohammadi MR, Tabrizi M, Ghaleiha A, Akhondzadeh S. Acetyl-L-carnitine as an adjunctive therapy in the treatment of attention-deficit/hyperactivity disorder in children and adolescents: A placebo-controlled trial. Child Psychiatry Hum Dev. 2011;42(3):367-75. [PubMed ID: 21336630]. https://doi.org/10.1007/s10578-011-0220-y.

  • 24.

    DuPaul GJ, Power TJ, Anastopoulos AD, Reid R. ADHD Rating Scale-IV: Checklists, norms, and clinical interpretation. New York, USA: Guilford Press; 1998.

  • 25.

    Modabbernia A, Sohrabi H, Nasehi AA, Raisi F, Saroukhani S, Jamshidi A, et al. Effect of saffron on fluoxetine-induced sexual impairment in men: Randomized double-blind placebo-controlled trial. Psychopharmacology (Berl). 2012;223(4):381-8. [PubMed ID: 22552758]. https://doi.org/10.1007/s00213-012-2729-6.

  • 26.

    Daughton JM, Kratochvil CJ. Review of ADHD pharmacotherapies: Advantages, disadvantages, and clinical pearls. J Am Acad Child Adolesc Psychiatry. 2009;48(3):240-8. [PubMed ID: 19242289]. https://doi.org/10.1097/CHI.0b013e318197748f.

  • 27.

    Durston S. A review of the biological bases of ADHD: What have we learned from imaging studies? Ment Retard Dev Disabil Res Rev. 2003;9(3):184-95. [PubMed ID: 12953298]. https://doi.org/10.1002/mrdd.10079.

  • 28.

    Howells FM, Russell VA. Glutamate-stimulated release of norepinephrine in hippocampal slices of animal models of attention-deficit/hyperactivity disorder (spontaneously hypertensive rat) and depression/anxiety-like behaviours (Wistar-Kyoto rat). Brain Res. 2008;1200:107-15. [PubMed ID: 18295191]. https://doi.org/10.1016/j.brainres.2008.01.033.

  • 29.

    Ulke C, Rullmann M, Huang J, Luthardt J, Becker GA, Patt M, et al. Adult attention-deficit/hyperactivity disorder is associated with reduced norepinephrine transporter availability in right attention networks: A (S,S)-O-[(11)C]methylreboxetine positron emission tomography study. Transl Psychiatry. 2019;9(1):301. [PubMed ID: 31732713]. [PubMed Central ID: PMC6858438]. https://doi.org/10.1038/s41398-019-0619-y.

  • 30.

    Mueller A, Hong DS, Shepard S, Moore T. Linking ADHD to the neural circuitry of attention. Trends Cogn Sci. 2017;21(6):474-88. [PubMed ID: 28483638]. [PubMed Central ID: PMC5497785]. https://doi.org/10.1016/j.tics.2017.03.009.

  • 31.

    Kowalczyk OS, Cubillo AI, Smith A, Barrett N, Giampietro V, Brammer M, et al. Methylphenidate and atomoxetine normalise fronto-parietal underactivation during sustained attention in ADHD adolescents. Eur Neuropsychopharmacol. 2019;29(10):1102-16. [PubMed ID: 31358436]. https://doi.org/10.1016/j.euroneuro.2019.07.139.

  • 32.

    Strauss M, Ulke C, Paucke M, Huang J, Mauche N, Sander C, et al. Brain arousal regulation in adults with attention-deficit/hyperactivity disorder (ADHD). Psychiatry Res. 2018;261:102-8. [PubMed ID: 29291475]. https://doi.org/10.1016/j.psychres.2017.12.043.

  • 33.

    Hesse S, Becker GA, Rullmann M, Bresch A, Luthardt J, Hankir MK, et al. Central noradrenaline transporter availability in highly obese, non-depressed individuals. Eur J Nucl Med Mol Imaging. 2017;44(6):1056-64. [PubMed ID: 28066877]. [PubMed Central ID: PMC5538358]. https://doi.org/10.1007/s00259-016-3590-3.

  • 34.

    Sharma A, Couture J. A review of the pathophysiology, etiology, and treatment of attention-deficit hyperactivity disorder (ADHD). Ann Pharmacother. 2014;48(2):209-25. [PubMed ID: 24259638]. https://doi.org/10.1177/1060028013510699.

  • 35.

    Mohammadi MR, Akhondzadeh S. Pharmacotherapy of attention-deficit/hyperactivity disorder: nonstimulant medication approaches. Expert Rev Neurother. 2007;7(2):195-201. [PubMed ID: 17286552]. https://doi.org/10.1586/14737175.7.2.195.

  • 36.

    Ríos JL, Recio MC, Giner RM, Máñez S. An update review of saffron and its active constituents. Phytother Res. 1996;10(3):189-93. https://doi.org/10.1002/(sici)1099-1573(199605)10:3<189::aid-ptr754>3.0.co;2-c.

  • 37.

    Khazdair MR, Boskabady MH, Hosseini M, Rezaee R, M. Tsatsakis A. The effects of Crocus sativus (saffron) and its constituents on nervous system: A review. Avicenna J Phytomed. 2015;5(5):376-91. [PubMed ID: 26468457]. [PubMed Central ID: PMC4599112].

  • 38.

    Georgiadou G, Grivas V, Tarantilis PA, Pitsikas N. Crocins, the active constituents of Crocus sativus L., counteracted ketamine-induced behavioural deficits in rats. Psychopharmacology (Berl). 2014;231(4):717-26. [PubMed ID: 24096536]. https://doi.org/10.1007/s00213-013-3293-4.

  • 39.

    Pitsikas N, Tarantilis PA. Crocins, the active constituents of Crocus sativus L., counteracted apomorphine-induced performance deficits in the novel object recognition task, but not novel object location task, in rats. Neurosci Lett. 2017;644:37-42. [PubMed ID: 28216334]. https://doi.org/10.1016/j.neulet.2017.02.042.

  • 40.

    Fadai F, Mousavi B, Ashtari Z, Ali beigi N, Farhang S, Hashempour S, et al. Saffron aqueous extract prevents metabolic syndrome in patients with schizophrenia on olanzapine treatment: A randomized triple blind placebo controlled study. Pharmacopsychiatry. 2014;47(4-5):156-61. [PubMed ID: 24955550]. https://doi.org/10.1055/s-0034-1382001.

  • 41.

    Mousavi B, Bathaie SZ, Fadai F, Ashtari Z, Ali Beigi N, Farhang S, et al. Safety evaluation of saffron stigma (Crocus sativus L.) aqueous extract and crocin in patients with schizophrenia. Avicenna J Phytomed. 2015;5(5):413-9. [PubMed ID: 26468460]. [PubMed Central ID: PMC4599113].

  • 42.

    Pitsikas N. The Effect of Crocus sativus L. and Its constituents on memory: Basic studies and clinical applications. Evid Based Complement Alternat Med. 2015;2015:926284. [PubMed ID: 25713594]. [PubMed Central ID: PMC4331467]. https://doi.org/10.1155/2015/926284.

  • 43.

    Ehsanifar M, Tameh AA, Farzadkia M, Kalantari RR, Zavareh MS, Nikzaad H, et al. Exposure to nanoscale diesel exhaust particles: Oxidative stress, neuroinflammation, anxiety and depression on adult male mice. Ecotoxicol Environ Saf. 2019;168:338-47. [PubMed ID: 30391838]. https://doi.org/10.1016/j.ecoenv.2018.10.090.

  • 44.

    Finley JW, Gao S. A perspective on Crocus sativus L. (saffron) constituent crocin: A potent water-soluble antioxidant and potential therapy for Alzheimer's disease. J Agric Food Chem. 2017;65(5):1005-20. [PubMed ID: 28098452]. https://doi.org/10.1021/acs.jafc.6b04398.

  • 45.

    Curatolo P, Paloscia C, D'Agati E, Moavero R, Pasini A. The neurobiology of attention deficit/hyperactivity disorder. Eur J Paediatr Neurol. 2009;13(4):299-304. [PubMed ID: 18644740]. https://doi.org/10.1016/j.ejpn.2008.06.003.

  • 46.

    Sarris J, Kean J, Schweitzer I, Lake J. Complementary medicines (herbal and nutritional products) in the treatment of attention deficit hyperactivity disorder (ADHD): A systematic review of the evidence. Complement Ther Med. 2011;19(4):216-27. [PubMed ID: 21827936]. https://doi.org/10.1016/j.ctim.2011.06.007.

  • 47.

    Bian Y, Zhao C, Lee SM. Neuroprotective potency of saffron against neuropsychiatric diseases, neurodegenerative diseases, and other brain disorders: From bench to bedside. Front Pharmacol. 2020;11:579052. [PubMed ID: 33117172]. [PubMed Central ID: PMC7573929]. https://doi.org/10.3389/fphar.2020.579052.

  • 48.

    Jia YF, Wininger K, Ho AM, Peyton L, Baker M, Choi DS. Astrocytic glutamate transporter 1 (GLT1) deficiency reduces anxiety- and depression-like behaviors in mice. Front Behav Neurosci. 2020;14:57. [PubMed ID: 32390810]. [PubMed Central ID: PMC7189218]. https://doi.org/10.3389/fnbeh.2020.00057.

  • 49.

    Fukui H, Toyoshima K, Komaki R. Psychological and neuroendocrinological effects of odor of saffron (Crocus sativus). Phytomedicine. 2011;18(8-9):726-30. [PubMed ID: 21242071]. https://doi.org/10.1016/j.phymed.2010.11.013.