Evaluating the Efficacy and Safety of Saffron Extracts on Attention deficit and hyperactivity disorder (ADHD) Treatment
Author : Mahsima Khaamooshi | 2024 Feb 29

Evaluating The Efficacy And Safety Of Saffron Extracts On Attention Deficit And Hyperactivity Disorder (Adhd) Treatment

Introduction The traditional plant, Crocus sativus, commonly known as saffron, is renowned for its potential therapeutic benefits. This study aims to assess the effectiveness and safety of saffron extracts in treating attention deficit hyperactivity disorder (ADHD).

Methodology Our research includes clinical trials that evaluated the efficacy and safety of saffron in treating ADHD. We excluded non-English papers, review articles, commentaries, letters, observational studies, theses, animal studies, in-vitro studies, and conference abstracts. The risk of bias in randomized studies was assessed using the Cochrane RoB.2 tool, while the ROBINS-I tool was used to evaluate the risk of bias in pre-post intervention studies.

Results Out of the studies reviewed, four met our inclusion criteria, encompassing a total of 118 patients. The findings indicated that saffron could effectively serve as an adjuvant therapy to Methylphenidate (MPH) or as a standalone treatment for ADHD, without significant safety concerns.

Discussion Saffron shows promising potential in alleviating ADHD symptoms and has an acceptable safety profile. We recommend future multicenter studies that are well-designed to further investigate this potential.


ADHD is one of the most common neurodevelopmental disorders among children, with a prevalence of 3% to 7% (Castells et al., 2011), and it is reported to persist during adulthood in 15% to 50% (Faraone et al., 2006; Lara et al., 2009). The prevalence of ADHD in adults is about 2.5% to 5% (Sayal et al., 2018; Thomas et al., 2015).

The symptoms of ADHD in children include inattention, hyperactivity, and impulsivity. Inattention is commonly demonstrated as distractibility, straining in sustaining attention on activities, trouble in organizing tasks and activities as well as forgetfulness. Hyperactivity or impulsivity symptoms mostly include being fidgety, interrupting others’ speech, inability to be still, inappropriate movements, and excessive talking (Posner et al., 2020; Thapar & Cooper, 2016; Wolraich et al., 2019). Patients with ADHD need a comprehensive treatment covering behavioral, psychological, and educational needs (Dalrymple et al., 2020). Pharmacological treatments consist of stimulants such as methylphenidate (MPH/ Ritalin©), and non-stimulant drugs such as atomoxetine and guanfacine (Caye et al., 2019; Toomey et al., 2012).

The medical use of alternative methods, especially herbs, goes back to hundred years ago (Modabbernia & Akhondzadeh, 2013). In this regard, one of the most popular traditional plants, best known for its culinary and coloring use in Asian and European countries, is Crocus sativus also known as saffron. Based on recent studies, saffron as an herbal remedy is believed to have antispasmodic, antitumor, antihypertensive, anticholinergic, anticoagulant, antidepressant, antiseptic, and anticonvulsant effects (Bathaie & Mousavi, 2010; Srivastava et al., 2010). Saffron plays a role as an N-methyl-D-aspartic acid (NMDA) receptor antagonist and gamma-aminobutyric acid (GABA)- agonist by increasing the dopamine and norepinephrine reuptake inhibition (Wang et al., 2010). It is also believed to have a beneficial effect in ameliorating anxiety and depression and improving memory functions (Baziar et al., 2019; Ross, 2020). In general, saffron might be useful as an antidepressant agent in alleviating ADHD symptoms (Curatolo et al., 2009; Sarris, 2007).

Dutta et al. investigated the advancement in the evi- evidence-based use of herbal remedies for ADHD. The useful- ness of saffron had only been assessed in one of the included articles of this study (Dutta et al., 2022); however, there are more published articles discussing the effectiveness of saffron (Baziar et al., 2019; Blasco-Fontecilla et al., 2022; Khaksarian et al., 2021; Pazoki et al., 2022). This study aims to systematically evaluate the safety and efficacy of saffron in patients with ADHD.


This systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) 2020 statement (Page et al., 2021).

Eligibility Criteria

Interventional studies that investigated the safety and/or efficacy of saffron, as the main remedy or a supplement, in patients with ADHD, with or without a control group, were included in this systematic review. Non-English papers, review articles, commentaries, letters, observational studies, thesis, animal studies, in-vitro studies, and conference abstracts, were not included.


A systematic search was conducted in Medline via PubMed, Embase, Scopus, and Web of Science in November 2022, with the following strategy for PubMed: (Crocus [Mesh] OR Saffron OR Crocus) AND (attention deficit disorder with hyperactivity [Mesh] OR (Attention Deficit) OR ADHD OR Hyperkinetic OR (Minimal Brain Dysfunction) OR ADDH), with no limitations or filters. Also, for the comprehensive inclusion of the published studies, reference lists of the articles were checked.

Study Selection

The results of database searches were imported into EndNote software and after removing the duplicated results, two independent researchers (SS-S and AN) assessed the meeting eligibility criteria in two title/abstract and full-te

 stages. Disagreements in the study selection process were resolved through consultation or by referring to another author (SS or SF).

Data Collection

Data extraction was conducted using an electronic table in Microsoft Excel by two authors (SS-S and AN) which included the following parameters: the name of the first author of the study, the publication year, study design, set- ting of the study, inclusion and exclusion criteria, Interventions and the number of patients (Female /male), age (mean, SD), outcomes, and timings of assessing the outcomes and final conclusion.

Risk of Bias Assessment and Certainty of the Evidence

The second version of the Cochrane risk of bias tool (RoB.2) was chosen for the assessment of Randomized Controlled Trial (RCT) studies in five domains. The first domain evaluates the randomization process, the second domain assesses the deviations from intended interventions, the third domain examines the missing outcome data, the fourth domain is for measures of the outcome and the fifth domain assesses the selection of the reported results (Sterne et al., 2019). The assessment of the pre-post intervention study was done using The Risk of Bias in Non-Randomized Studies—of Interventions (ROBINS-I) assessment tool. This tool assesses the bias due to confounding, the bias in the selection of participants into the study, bias in the classification of interventions, bias due to deviations from intended interventions, bias due to missing data, bias in the measurement of outcomes, bias in the selection of the reported result. In the end, an overall bias shows the risk of bias in the included studies (Sterne et al., 2016). Risk of bias assessments were conducted by two researchers (SS-S and AN) and disagreements were referred to a third researcher (SF or SS). In addition, the Consolidated Standards of Reporting Trials (CONSORT) 2010 checklist was used to assess the quality of reported information in included RCT studies (Schulz et al., 2010). Finally, the overall certainty of the evidence was evaluated using the GRADE approach. This evidence grading system categorized the confidence in the effect estimates as either “high,” “moderate,” “low,” or “very low” for each outcome. This categorization is based on judgment, but the process of making these judgments follows a transparent structure. (Schünemann et al., 2019).


Search Results and Selection Process

The PRISMA flow diagram shows the details of the selection process (Figure 1). In summary, after removing duplications, 32 articles were assessed in the title/abstract stage, and finally, four articles met the inclusion criteria (Baziar et al., 2019; Blasco-Fontecilla et al., 2022; Khaksarian et al., 2021; Pazoki et al., 2022) and two review articles were excluded in the full-text stage (Ozsavci et al., 2019; Ross, 2020).

Figure 1. PRISMA 2020 flow diagram for new systematic reviews.

Quality Assessment, Risk of Bias, and Certainty of the Evidence

Supplemental Material 1 is the CONSORT checklists for the included RCTs and Figures 2 and 3 present the results of the risk of bias assessments. The most common source of bias in included RCTs was due to the selection of the reported result. Also, in the non-randomized intervention study, dealing with the selection of participants, deviations from intended interventions, outcome measures, and selection of the reported results were the main sources of bias. Assessing certainty of the evidence indicates a high level of confidence in the results for two studies (Baziar et al., 2019; Khaksarian et al., 2021), while suggests a lower level of confidence for two others (Blasco-Fontecilla et al., 2022; Pazoki et al., 2022).

Characteristics of the Included Studies

Out of the four included studies, three were RCTs and the rest were a pre-post-intervention study. Three of the studies were conducted in Iran and the rest was done in Spain. The publication years were from 2019 to 2022. Participants were children and adolescents aged 6 to 16 years in three studies and adults aged 20 to 60 years in one study. The eligibility criteria of the participants in each study are summarized in Table 1. Two of the included studies assessed the efficacy of saffron in comparison with MPH and two studies evaluated the potency of saffron treatment combined with MPH in comparison with MPH alone.

Summary of Findings

Pazoki et al. evaluated the efficacy and safety of saffron as an adjuvant to MPH for improving symptoms in adults with ADHD. In this study, 56 patients, were assigned into two parallel groups and randomly received MPH (30 mg/day) plus placebo or MPH plus saffron (15 mg twice daily) for 6 weeks. The adult ADHD self-report scale change from baseline to the sixth week was significantly different between the saffron and placebo groups. Also, in terms of side effects (including insomnia, headache, abdominal pain, decreased appetite, nausea, itching, and cough), there was no significant difference between the groups (Pazoki et al., 2022).

Baziar et al. compared the efficacy and safety of saffron and MPH in children suffering from ADHD. For this purpose, 54 patients were randomly assigned to receive either 20 to 30 mg/day MPH or 20 to 30 mg/day saffron capsules (depending on weight) for 6 weeks. Teacher and Parent Attention-Deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) was used to assessing the symptoms in baseline, third week, and sixth week. This study demonstrated that changes in ADHD-RS-IV score from baseline were not significantly different between the saffron group and the MPH group. In addition, there was no significant difference in terms of the frequency of side effects (Baziar et al., 2019).

Khaksarian et al. evaluated the effectiveness of MPH and its combination with saffron. Seventy children were enrolled in their study and randomly assigned into two groups. Both groups received 20 or 30 mg/day of MPH and one of the groups also received 20 or 30 mg/day of saffron in a capsule based on body mass index. Symptoms of patients were evaluated using the ADHD-RS-IV at baseline and after 4 and 8 weeks of treatment. After 8 weeks, there was no crucial difference between the MPH and MPH plus saffron groups in terms of side effects. Besides, during 8 and 4 weeks of treatment, the symptoms of patients decreased meaningfully. In this study saffron, as a supplementation, was found to add beneficial effects to MPH in patients with ADHD (Khaksarian et al., 2021).