Methylphenidate and amphetamine do not induce cytogenetic damage in lymphocytes of children with ADHD.

National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Triangle Park, NC 27709, USA.
Journal of the American Academy of Child and Adolescent Psychiatry (Impact Factor: 6.35). 11/2008; 47(12):1375-83. DOI: 10.1097/CHI.0b013e3181893620
Source: PubMed

ABSTRACT In response to previously published findings of methylphenidate-induced chromosomal changes in children, this study was designed to determine whether methylphenidate- or 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.
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.
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.
Earlier findings of methylphenidate-induced chromosomal changes in children were 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.

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    ABSTRACT: The stimulants methylphenidate and amphetamine are used to treat children with attention deficit/hyperactivity disorder over important developmental periods, prompting concerns regarding possible long-term health impact. This study assessed the effects of such a regimen in male, peri-adolescent rhesus monkeys on a variety of cognitive/behavioral, physiological, and in vivo neurochemical imaging parameters. Twice daily (0900 and 1200 hours), for a total of 18 months, juvenile male monkeys (8 per group) consumed either an unadulterated orange-flavored solution, a methylphenidate solution, or a dl-amphetamine mixture. Doses were titrated to reach blood/plasma levels comparable to therapeutic levels in children. [(11)C]MPH and [(11)C]raclopride dynamic PET scans were performed to image dopamine transporter and D(2)-like receptors, respectively. Binding potential (BP(ND)), an index of tracer-specific binding, and amphetamine-induced changes in BP(ND) of [(11)C]raclopride were estimated by kinetic modeling. There were no consistent differences among groups on the vast majority of measures, including cognitive (psychomotor speed, timing, inhibitory control, cognitive flexibility), general activity, physiological (body weight, head circumference, crown-to-rump length), and neurochemical (ie, developmental changes in dopamine transporter, dopamine D(2) receptor density, and amphetamine-stimulated dopamine release were as expected). Cytogenetic studies indicated that neither drug was a clastogen in rhesus monkeys. Thus, methylphenidate and amphetamine at therapeutic blood/plasma levels during peri-adolescence in non-human primates have little effect on physiological or behavioral/cognitive development.
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    ABSTRACT: Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / m o l m u t C o m m u n i t y a d d r e s s : w w w . e l s e v i e r . c o m / l o c a t e / m u t r e s a b s t r a c t Attention-deficit/hyperactivity disorder (ADHD) is the most common psychiatric condition with onset in childhood, and in more than 50% of cases it persists into adulthood as a chronic disorder. Over five million methylphenidate (MPH) prescriptions were issued in the USA in 2003, mostly for children. A previous report [ Cytogenetic effects in children treated with methylphenidate, Cancer Lett. 230 (2005) 284–291.] described the induction of chromosome abnormalities by MPH in children treated for three months, contrary to most of the in vitro and in vivo studies reported since then. We present new relevant information concerning the cytogenetic effects of MPH in children and adults. We include a prospective sample of 12 children and 7 adults with a new diagnosis of ADHD and naive to MPH. We analyzed the cytogenetic effects on peripheral lymphocytes before and three months after starting MPH therapy. The cytogenetic analyses included a cytokinesis-block micronucleus (CBMN) assay, a sister chromatid exchange (SCE) analysis and the determination of chromosome aberrations (CA). Following the same strategy and analyzing the same cytogenetic endpoints that were investigated in the original report [R. Cytogenetic effects in children treated with methylphenidate, Cancer Lett. 230 (2005) 284–291.], we found no evidence of increased frequency of micronuclei, sister chromatid exchanges or chromosome aberrations induced by MPH in children and adult populations. MPH treatment of children and adults with ADHD resulted in no significant genomic damage (as suggested by the three endpoints studied), results that do not support a potential increased risk of cancer after exposure to MPH.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 06/2009; 666:44-49. DOI:10.1016/j.mrfmmm.2009.03.014 · 4.44 Impact Factor
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    ABSTRACT: Abstract Objective: A study on chromosomal abnormalities has raised concerns that medication with methylphenidate (MPH) for attention-deficit/hyperactivity disorders (ADHD) might increase the risk of cancer. We performed a rigorous test of the association between cancer and MPH and other drugs used for ADHD, based on data from nationwide Danish registers. Methods: Data were linked from five registers containing information on a total of 21,186 patients with ADHD, their drug prescription rates, and associated cancer diagnoses between 1994 and 2010. The cohort included subgroups treated with MPH only, amphetamines only, other ADHD-specific drugs only, antidepressants only, antipsychotics only, mixed medication, and a control group of patients with ADHD who had never taken medication. Frequencies of cancer diagnoses in these groups were compared. In addition, hazard risk (HR) ratios for developing cancer, and survival rates in these subgroups, were analyzed. Results: The mean observation time varied between 1.3 and 10.8 years for the various drugs. Cancer rates in the total group amounted to 1.27 per 10 000 person-years before and to 4.33 per 10 000 person-years after onset of treatment. The frequency of cancer was significantly higher (p=0.05) after than before medication only in the antipsychotics subgroup. Furthermore, for mixed medication, the cancer frequency in a small subgroup was significantly higher (p<0.05) after onset of medication than in the unmedicated subgroup. The Cox regression analysis indicated that none of the drugs represented risk factors, whereas higher dose (p<0.001) and older age (p<0.05) were risk factors for developing cancer. Conclusions: The concern that children taking MPH and other drugs over long periods of time could be at a significant risk of developing cancer is not substantiated by these findings in a large and representative sample, which had been diagnosed and treated over a period of 17 years.
    Journal of child and adolescent psychopharmacology 04/2013; 24(2). DOI:10.1089/cap.2012.0050 · 3.07 Impact Factor

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