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Reviewed: Baziar S, Aqamolaei A, Khadem 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):205-212. doi: 10.1089/cap.2018.0146.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common mental disorders in children and adolescents. Although the pathophysiology has not been fully determined, evidence suggests it involves malfunction of monoaminergic and glutamatergic neurotransmitter systems. The first line of treatment for ADHD is pharmacotherapy with stimulants such as methylphenidate (MPH; Ritalin^®; Novartis Pharmaceuticals; Basel, Switzerland). However, approximately 30% of patients do not respond to treatment or cannot tolerate the adverse effects (AEs). Among the non-stimulant therapies that have been assessed, antidepressant drugs have been reported to improve ADHD symptoms, but these therapeutics also are associated with significant AEs. Dried stigmas of saffron (Crocus sativus, Iridaceae) may be a safe and effective treatment option for ADHD. Saffron has clinically demonstrated antidepressant and anxiolytic effects, and in experimental studies, it has shown neuroprotective properties, learning and memory enhancement, and modulation of monoaminergic and glutamatergic systems. The purpose of this randomized, double-blind, controlled pilot study was to compare the efficacy and safety of saffron and MPH in children and adolescents with ADHD.

Boys and girls (N = 54; 6-17 years old) with ADHD according to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) were recruited from the outpatient child and adolescent psychiatry clinics at Roozbeh Psychiatric Hospital (affiliated with Tehran University of Medical Sciences) in Tehran, Iran. Included patients had total and/or subscale scores on the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) of at least 1.5 standard deviations above norms for patient age and gender. Excluded patients had psychiatric comorbidities (except for oppositional defiant disorder); intellectual development disorder (defined as having an IQ < 70); a clinically significant chronic medical condition (such as epilepsy, organic brain disorders, or cardiac abnormalities); systolic blood pressure greater than 125 mmHg and/or resting pulse rate below 60 beats/min or above 110 beats/min; a history of allergy to saffron; psychotropic medication use in the previous two weeks; any anti-coagulant drug or herbal supplement use that might adversely react with saffron; were pregnant or lactating; or were scheduled to undergo surgery within 14 days.

Patients were randomly assigned to receive either 20-30 mg/day saffron depending on body weight (20 mg/day for < 30 kg and 30 mg/day for > 30 kg) or escalating doses of MPH for six weeks. The manufacturer of the 10-mg saffron capsules and the chemical characteristics of the saffron were not reported. MPH was initiated at a dose of 0.3-1 mg/kg/day and titrated up to 10 mg/day in week one, 20 mg/day in week two, and in weeks three through six, 20 mg/day for children < 30 kg and 30 mg/day for children > 30 kg. Parents and teachers completed ADHD-RS-IV ratings at baseline, three weeks, and six weeks. The primary outcome measure was the change in scores on the parent version of the ADHD-RS-IV. Secondary outcome measures were the change in scores on the teacher version of the ADHD-RS-IV and response rates (defined as ≥ 40% decrease from baseline to six weeks) on the parent and teacher ADHD-RS-IV ratings.

Baseline characteristics did not significantly differ between groups. Twenty-five patients in each group completed the study; two patients in each group were discontinued because consent was withdrawn. Changes in parent and teacher ADHD-RS-IV scores indicated both the saffron and MPH groups experienced significant improvements in hyperactivity and inattention at three weeks (P < 0.001 for both groups), and these benefits were maintained through to six weeks. At six weeks, changes in parent and teacher ADHD-RS-IV scores did not significantly differ between groups.

Based on the parent ratings, there were no significant between-group differences in response rates (100% in the saffron group and 96% in the MPH group) or the percentage of patients exhibiting marked improvement (96% of the saffron group and 84% of the MPH group), which was defined as a decrease in ADHD-RS-IV scores of at least 50%.

The teacher ratings indicated a much lower response rate (52% in the saffron group and 56% in the MPH group) and a much lower percentage of patients showing marked improvement (40% of the saffron group and 48% of the MPH group). However, the differences between groups were not significant. No serious AEs were reported, and the incidence of AEs did not significantly differ between groups.

The authors concluded that 20-30 mg/day saffron for six weeks was comparable to MPH for the treatment of ADHD. Acknowledged limitations of the study include the lack of a placebo control, relatively small sample size, lack of neurocognitive tests, and short treatment duration. In addition, no information was provided about concentrations of important constituents (e.g., crocins, safranal, and picrocrocin), which are known to differ depending on the saffron variety. Larger and longer placebo-controlled studies are warranted to confirm these findings.