Effect of Methylphenidate and Folic Acid on ADHD Symptoms and Quality of Life and Aggression: A Randomized Double Blind Placebo Controlled Clinical Trial

  • Ahmad Ghanizadeh Mail Research Center for Psychiatry and Behavioral Sciences Shiraz University of Medical Sciences, Shiraz, Iran ; Department of Psychiatry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
  • Zohreh Sayyari Research Center for Psychiatry and Behavioral Sciences Shiraz University of Medical Sciences, Shiraz, Iran
  • Mohammad Reza Mohammadi Department of Psychiatry, Psychiatry and Psychology Research Center, Tehran university of Medical Sciences. Tehran, Iran
Aggression, Attention deficit hyperactivity disorder, child, clinical trial, folic acid, methylphenidate, quality of life, therapeutics


Objective: This clinical trial examines the effect of augmentation of methylphenidate (MPH) with folic acid to improve quality of life, and to treat aggression and ADHD symptoms .
Participants of this eight week randomized double blind placebo controlled clinical trial were 49 children with ADHD. They were randomly assigned into one of the two groups: the first group receiving methylphenidate (10 to 20mg/day) plus folic (5mg/day), and the second group receiving methylphenidate plus placebo. Parent-reported ADHD symptoms and Overt Aggression Scale score were the outcome measures. Quality of life was assessed as well. Assessments were performed at pre-intervention, and at one month and two months after starting the interventions using repeated measure analysis .
The mean age of children was 9.6(2.7) years. Age and gender were not associated with the groups. ADHD symptoms significantly decreased in both groups during the trial. However, no difference was observed between the groups. Moreover, ag ression non-significantly decreased in both groups. Meanwhile, there was no difference between the two groups in efficacy for treating different types of aggressive behaviors including: verbal aggression, physical aggression against people, physical aggression against properties or objects, and aggression against self (self-injurious behavior). While methylphenidate improved quality of life of children with ADHD, folic acid did not improve it more than placebo. Both medications were well tolerated.
Conclusion: considering the marked limitations of this trial, this primarily report suggests that methylphenidate may improve ADHD symptoms and the quality of life of children with ADHD. Current evidence does not support that folic acid as an adjuvant is effective for treating ADHD symptoms or aggression, or the improving quality of life of children with ADHD.


Matsuura N, Hashimoto T, Toichi M. The Characteristics of Ad/Hd Symptoms, Self-Esteem, and Aggression among Serious Juvenile Offenders in Japan. Res Dev Disabil 2010; 31: 1197-1203.

Ghanizadeh A, Nouri SZ, Nabi SS. Psychiatric problems and suicidal behaviour in incarcerated adolescents in the Islamic Republic of Iran. Eastern Mediterranean health journal = La revue de sante de la Mediterranee orientale = al-Majallah al-sihhiyah li-sharq al-mutawassit 2012; 18: 311-7.

Keune PM, Schonenberg M, Wyckoff S, Mayer K, Riemann S, Hautzinger M, et al. Frontal Alpha-Asymmetry in Adults with Attention Deficit Hyperactivity Disorder: Replication and Specification. Biological psychology 2011; 87: 306-310.

Doerfler LA, Connor DF, Toscano PF, Jr. Aggression, Adhd Symptoms, and Dysphoria in Children and Adolescents Diagnosed with Bipolar Disorder and Adhd. J Affect Disord 2011; 131: 312-319.

King S, Waschbusch DA. Aggression in Children with Attention-Deficit/Hyperactivity Disorder. Expert Rev Neurother 2010; 10: 1581-1594.

List BA, Barzman DH. Evidence-Based Recommendations for the Treatment of Aggression in Pediatric Patients with Attention Deficit Hyperactivity Disorder. The Psychiatr Q 2011; 82: 33-42.

Tseng WL, Kawabata Y, Gau SS, Banny AM, Lingras KA, Crick NR. Relations of Inattention and Hyperactivity/Impulsivity to Preadolescent Peer Functioning: The Mediating Roles of Aggressive and Prosocial Behaviors. J Clin Child Adolesc Psychol 2012; 41: 275-287.

Connor DF, Ford JD. Comorbid Symptom Severity in Attention-Deficit/Hyperactivity Disorder: A Clinical Study. J Clin Psychiatry 2012; 73: 711-717.

Krull KR, Brouwers P, Jain N, Zhang L, Bomgaars L, Dreyer Z, et al. Folate Pathway Genetic Polymorphisms Are Related to Attention Disorders in Childhood Leukemia Survivors. J Pediatr 2008; 152: 101-105.

Schlotz W, Jones A, Phillips DI, Gale CR, Robinson SM and Godfrey KM. Lower Maternal Folate Status in Early Pregnancy Is Associated with Childhood Hyperactivity and Peer Problems in Offspring. J Child Psychol Psychiatry 2010; 51: 594-602.

Patrick LR. Restless Legs Syndrome: Pathophysiology and the Role of Iron and Folate. Altern Med Rev 2007; 12: 101-112.

Ghanizadeh A Namazi MR. A Possible Research and Clinical Implication of Association of Homocysteine and Glutamate Levels in Brain for Management of Aggression. Int J Dev Neurosci 2010; 28: 125.

Chan A, Tchantchou F, Graves V, Rozen R, Shea TB. Dietary and Genetic Compromise in Folate Availability Reduces Acetylcholine, Cognitive Performance and Increases Aggression: Critical Role of S-Adenosyl Methionine. The journal of nutrition, health & aging 2008; 12: 252-261.

Wigal T, Greenhill L, Chuang S, McGough J, Vitiello B, Skrobala A, et al. Safety and Tolerability of Methylphenidate in Preschool Children with Adhd. J Am Acad Child Adolesc Psychiatry 2006; 45: 1294-1303.

Ghanizadeh A. A systematic review of the efficacy and safety of desipramine for treating ADHD. Current drug safety. 2013; 8: 69-74.

Ibrahim W, Tousson E, El-Masry T, Arafa N and Akela M. The Effect of Folic Acid as an Antioxidant on the Hypothalamic Monoamines in Experimentally Induced Hypothyroid Rat. Toxicol Ind Health 2012; 28: 253-261.

Blader JC, Pliszka SR, Jensen PS, Schooler NR, Kafantaris V. Stimulant-Responsive and Stimulant-Refractory Aggressive Behavior among Children with Adhd. Pediatrics 2010; 126: 796-806.

Ghanizadeh A, Jafari P. Cultural Structures of the Persian Parents' Ratings of Adhd. Journal of attention disorders 2010; 13: 369-373.

Yudofsky SC, Silver JM, Jackson W, Endicott J, Williams D. The Overt Aggression Scale for the Objective Rating of Verbal and Physical Aggression. Am J Psychiatry 1986; 143: 35-39.

Jafari P, Ghanizadeh A, Akhondzadeh S, Mohammadi MR. Health-Related Quality of Life of Iranian Children with Attention Deficit/Hyperactivity Disorder. Qual Life Res 2011; 20: 31-36.

Pappadopulos E, Woolston S, Chait A, Perkins M, Connor DF, Jensen PS. Pharmacotherapy of Aggression in Children and Adolescents: Efficacy and Effect Size. Journal of the Canadian Academy of Child and Adolescent Psychiatry = Journal de l'Academie canadienne de psychiatrie de l'enfant et de l'adolescent 2006; 15: 27-39.

How to Cite
Ghanizadeh A, Sayyari Z, Mohammadi MR. Effect of Methylphenidate and Folic Acid on ADHD Symptoms and Quality of Life and Aggression: A Randomized Double Blind Placebo Controlled Clinical Trial. Iran J Psychiatry. 8(3):108-12.