Methylphenidate and Amphetamine Do Not Induce Cytogenetic Damage in Lymphocytes of Children With ADHD

Abstract

Objective-In response to previously published findings of methylphenidate-induced chromosomal changes in children, this study was designed to determine whether methylphenidateor amphetamine-based drugs induce chromosomal damage (structural aberrations, micronuclei, and sister chromatid exchanges) in peripheral blood lymphocytes of children with attention-deficit/ hyperactivity disorder after 3 months of continuous treatment.Method-Stimulant drug-naïve subjects, 6 to 12 years of age, in good overall health, and judged to be appropriate candidates for stimulant therapy based on rigorously diagnosed ADHD using DSM-IV criteria, were randomized into two open-label treatment groups (methylphenidate or mixed amphetamine salts). Each subject provided a blood sample before initiation of treatment and after 3 months of treatment. Pretreatment and posttreatment frequencies of chromosomal aberrations, micronuclei, and sister chromatid exchanges were determined for each subject.Results-Sixty-three subjects enrolled in the study; 47 subjects completed the full 3 months of treatment, 25 in the methylphenidate group and 22 in the amphetamine group. No significant treatment-related increases were observed in any of the three measures of cytogenetic damage in the 47 subjects who completed treatment or the 16 subjects who did not. Conclusions-Earlier findings of methylphenidate-induced chromosomal changes in childrenwere not replicated in this study. These results add to the accumulating evidence that therapeutic levels of methylphenidate do not induce cytogenetic damage in humans. Furthermore, our results indicate that amphetamine-based products do not pose a risk for cytogenetic damage in children. Although the use of these products has been associated with a number of manageable adverse effects (appetite suppression, insomnia, nervousness, headache, and dry mouth) and concern has been raised over potential adverse cardiovascular effects, their overall safety profiles are good. [7][8][9][10][11] However, the safety of MPH was abruptly challenged in 2005 by a report of increased frequencies of sister chromatid exchanges (SCE; indicative of DNA damage), structural chromosomal aberrations (CA), and micronuclei (MN; biomarkers of numerical and structural chromosomal changes) in lymphocytes of 12 pediatric patients with ADHD after 3 months of MPH-based drug therapy. 12 That study raised concern among members of the medical community and families of children with ADHD receiving MPH-based therapy because increased frequencies of CAs and micronuclei in peripheral blood lymphocytes are associated with an increased risk of cancer. 13,14 However, questions were raised regarding the study design and some of the reported findings, including the small sample size (12 children), a lack of critical details on blood sample processing and slide scoring, and the complete absence of SCE recorded in 6 of the 11 children analyzed for this endpoint. 15 The absence of SCE was especially troubling because such an observation has never been repor...

Flow cytometric detection of Pig‐A mutant red blood cells using an erythroid‐specific antibody: Application of the method for evaluating the in vivo genotoxicity of methylphenidate in adolescent rats

“…It is conceivable that if such a negative selection exists, it may disproportionately remove Pig-A mutants from treated rats, obscuring a small increase in mutant frequency. With these caveats in mind, our findings are consistent with an accumulating number of negative responses for MPH in in vivo genotoxicity assays [NTP, 1995;Manjanatha et al, 2008;Witt et al, 2008;Morris et al, 2009], many of which were conducted as a result of the positive findings reported by El-Zein et al [2005]. These data also indicate that agents that reduce erythropoiesis do not necessarily elevate Pig-A RBC mutant frequencies.…”

Safety of stimulant treatment in attention deficit hyperactivity disorder: part II

“…At 3 months, there were no cytogenetic changes in any of the children [133]. There have subsequently been concerns [133] raised about the methodology in the El-Zien study. Furthermore, an actual increased rate of cancer in those with ADHD has not been demonstrated [4].…”

“…There were some aberrations noted, but these were not consistent over time. A study [133] of 47 stimulant naive children ages 6 --12 diagnosed with ADHD who were treated with stimulants for 3 months at therapeutic doses of MPH and MAS did not find the children to have any increases in chromosomal damage. At 3 months, there were no cytogenetic changes in any of the children [133].…”

“…A study [133] of 47 stimulant naive children ages 6 --12 diagnosed with ADHD who were treated with stimulants for 3 months at therapeutic doses of MPH and MAS did not find the children to have any increases in chromosomal damage. At 3 months, there were no cytogenetic changes in any of the children [133]. There have subsequently been concerns [133] raised about the methodology in the El-Zien study.…”

The Investigation of Mutagenic and Carcinogenic Effects by the Ames Test

“…Fare lenfoma timidin kinaz testi, kromozomal mutasyonların yanı sıra gen mutasyonlarını da belirlediğinden, bu veriler MPH'nin klastojenik potansiyelinin değerlendirilmesi açısından önemli-dir. Bununla birlikte, Bonassi et al 2004 ve 2007 yıllarında yapmış oldukları çalışmalarda kromozomal aberasyon sıklığı ve periferik kan lenfositlerindeki mikroçekirdek artışının kanser riski ile ilişkisinin bildirilmesi ile tıp camiasında ve MPH tabanlı tedaviyi kabul eden DEHB'li çocukların ailelerinde tepkilere neden olmuştur (33)(34)(35).…”