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: 7.26). 11/2008; 47(12):1375-83. DOI: 10.1097/CHI.0b013e3181893620
Source: PubMed


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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    • "No significant effect of MPH treatment on any of the three endpoints was detected. Similarly, in a study sponsored by the US NIH, 25 children, diagnosed with ADHD according to DSM IV criteria and ranging in age from 6 to 12 years, were evaluated for the frequencies of MN, SCE and CA in peripheral blood lymphocytes before and after three months of treatment with normal therapeutic doses of MPH (18–54 mg per day at the end of 3 months of titration; Witt et al., 2008). No MPH-related increases in any of the three endpoints were detected. "
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    ABSTRACT: Attention deficit/hyperactivity disorder (ADHD), a common children's behavioral disorder, is characterized by inattention, hyperactivity and impulsivity. The disorder is thought to stem from abnormalities in the catecholamine pathway and the symptoms of the disorder have been successfully treated with methylphenidate (MPH) since the FDA approved the drug in the 1950s. MPH underwent the appropriate safety testing as part of the FDA approval process; however, a publication in 2005 that reported significant increases in cytogenetic damage in the lymphocytes of MPH-treated pediatric patients caused concern for patients and their families, the pharmaceutical industry and regulatory agencies. This communication will review the many studies that were subsequently initiated worldwide to address the genetic safety of MPH in both animal models and human subjects. Animal experiments broadened the study protocols used in the 2005 investigation to include a wider dose-range, a longer treatment period and automated scoring of biological endpoints, where possible, to reduce observer bias. The human subject studies replicated the experimental design used in the 2005 study, but increased the treatment periods and the sizes of the study populations. Neither the laboratory animal nor human subject studies found an increase in any of the measures of genetic damage that were evaluated. Taken together, these new studies are consistent with the original safety evaluation of the FDA and do not support the hypothesis that MPH treatment increases the risk of genetic damage in ADHD patients. Published 2012. This article is a US Government work and is in the public domain in the USA.
    Full-text · Article · Oct 2012 · Journal of Applied Toxicology
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    • "). However, the concern that psychostimulant use may increase the risk of substance abuse and smoking remains controversial (Witt et. al., 2008)."
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    ABSTRACT: Circadian pattern of activity regulates many aspects of mammalian physiology and behavior to particular times of the day by entraining the circadian clocks to external environmental signals. Since circadian rhythms are sensitive to many pharmacological agents, it is important to understand if the repetitive use of psychostimulants such as amphetamine will alter the circadian rhythm behavioral activity pattern. The present study uses male Sprague-Dawley rats to study the long-term effects of amphetamine on the locomotor circadian rhythm activity pattern. Rats were randomly assigned to a testing cage that recorded their locomotor activity nonstop for eleven days using the open field assay, as follows: one day of baseline activity was recorded and then the experimental group was injected with amphetamine (0.6mg/kg) for 6days, no treatment for 3days (i.e., washout days) and then re-challenged with amphetamine for one more day while the control group was treated similarly with saline. The Cosine Curve Statistical Analysis (CCSA) test was used to fit a 24-hour curve to activity pattern. Results indicate that repetitive daily amphetamine injections cause behavioral sensitization and a significant change of circadian rhythm of locomotor activity pattern, and elicit behavioral expectation to receive the drug or expression of withdrawal during the washout days. The results suggest that either changes in circadian rhythm caused sensitization and withdrawal or sensitization and withdrawal caused the change in circadian rhythm activity.
    Full-text · Article · Oct 2011 · Brain research
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    • "These findings raised concerns about the safety of MPH and warranted further investigation on the genotoxicity of this drug. Subsequent studies conducted in both humans and animal models in response to El-Zein et al.'s study [4] failed to support the initial findings of MPH-induced cytogenetic damage [5] [6] [7] [8] [9] [10]. Further, the results of the El-Zein study were inconsistent with previous studies indicating that MPH was negative in the Salmonella reversion assay [11] [12] and the p53 +/− mouse tumor bioassay [13]. "
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    ABSTRACT: Methylphenidate hydrochloride (MPH), a widely prescribed pediatric drug for attention deficit hyperactivity disorder, induced liver adenocarcinomas in B6C3F1 mice exposed to 500 ppm in feed for 2 years (Dunnick and Hailey (1995) [14]). In order to determine if the induction of liver tumors was by a mutagenic mode of action, groups of male Big Blue (BB) mice (B6C3F1 background) were fed diets containing 50-4000 ppm MPH for 4, 12, or 24 weeks. At sacrifice, the livers were removed and the cII mutant frequency (MF) and spectrum of cII mutations were determined. In addition, the frequencies of micronucleated reticulocytes (MN-RETs) and normochromatic erythrocytes (MN-NCEs) were measured in peripheral blood erythrocytes as was the Hprt MF in splenic lymphocytes. Food consumption and body weight gain/loss were recorded weekly for each animal. The levels of MPH and RA were determined immediately before sacrifice in the serum of mice fed MPH for 24 weeks. A significant loss in body weights (p <or= 0.01) was found in mice fed the 2000 and 4000 ppm doses of MPH; however, there was no significant difference in the food consumption by any of the MPH-treated groups. The average liver cII MF in control animals was 20 +/- 4.5 x 10(-6) where as in MPH-treated animals, the average cII MFs ranged between 20+/-2.5 and 32 +/- 6.7 x 10(-6). None of the cII MFs in livers from any of the MPH treatment was significantly higher than the concurrent controls at either 4, 12 or 24 weeks. Further, there was no significant increase in either the Hprt MF or the micronucleus frequency at any time point in the treated animals. These results suggest that MPH is not mutagenic in mice and that the induction of tumors as previously reported in the liver is probably through a nongenotoxic mode of action.
    Full-text · Article · Sep 2009 · Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
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