No increases in biomarkers of genetic damage or pathological changes in heart and brain tissues in male rats administered methylphenidate hydrochloride (Ritalin) for 28 days

Abstract

Following a 2005 report of chromosomal damage in children with attention deficit/hyperactivity disorder (ADHD) who were treated with the commonly prescribed medication methylphenidate (MPH), numerous studies have been conducted to clarify the risk for MPH-induced genetic damage. Although most of these studies reported no changes in genetic damage endpoints associated with exposure to MPH, one recent study (Andreazza et al. 2007) reported an increase in DNA damage detected by the Comet assay in blood and brain cells of Wistar rats treated by intraperitoneal injection with 1, 2, or 10 mg/kg MPH; no increases in micronucleated lymphocyte frequencies were observed in these rats. To clarify these findings, we treated adult male Wistar Han rats with 0, 2, 10, or 25 mg/kg MPH by gavage once daily for 28 consecutive days and measured micronucleated reticulocyte (MN-RET) frequencies in blood, and DNA damage in blood, brain, and liver cells 4 hr after final dosing. Flow cytometric evaluation of blood revealed no significant increases in MN-RET. Comet assay evaluations of blood leukocytes and cells of the liver, as well as of the striatum, hippocampus, and frontal cortex of the brain showed no increases in DNA damage in MPH-treated rats in any of the three treatment groups. Thus, the previously reported observations of DNA damage in blood and brain tissue of rats exposed to MPH for 28 days were not confirmed in this study. Additionally, no histopathological changes in brain or heart, or elevated serum biomarkers of cardiac injury were observed in these MPH-exposed rats.

Dose-response assessment of four genotoxic chemicals in a combined mouse and rat micronucleus (MN) and Comet assay protocol

“…This process of cryopreservation allowed for control of a uniform time interval between tissue collection and electrophoresis (Witt et al , 2009). Slides for the Comet assay were prepared from blood and minced tissue as follows.…”

Maternal and neonatal outcomes after exposure to ADHD medication during pregnancy: A systematic review and meta‐analysis

“…However, our subgroup analysis suggested that there might be a small increase in the risk of cardiovascular malformations associated with intrauterine exposure to MPH. Although very high doses of MPH have also been associated with certain malformations, most animal studies using relevant doses have not indicated a teratogenic effect . It should be noted that cardiovascular malformations might be associated with coexisting mental disorders and other associated factors rather than with exposure to MPH .…”

“…Although very high doses of MPH have also been associated with certain malformations, 29 most animal studies using relevant doses have not indicated a teratogenic effect. 30,31 It should be noted that cardiovascular malformations might be associated with coexisting mental disorders and other associated factors rather than with exposure to MPH. 32 We compared MPH-exposed pregnant women with unexposed pregnant women.…”

The Investigation of Mutagenic and Carcinogenic Effects by the Ames Test

“…Ancak, memeli hücre kültürü kullanılarak yapılmış olan MPH mutajenite testinde, herhangi bir mutajenik etkiye rastlanmamıştır (27,28). Kan ve beyin hücrelerindeki hipokampus ve stratiumdaki DNA hasar düzeyi incelenmiş ve bir hasar tespit edilmemiştir (29,30). MPH'nin in vitro uygulamasının DNA üzerine zararlı etkisi ile ilgili oldukça şüpheli verilerin aksine, Teo et al (2003) tarafından yayınlanan ve mevcut uluslararası kurallara göre yürütülen fare lenfoma deneyi ile açıkça negatif sonuçlar elde edilmiş ve bu çalışma, in vitro memeli hücrelerinde MPH'nin genotoksik potansiyeli olmadığına dair önemli bir gösterge olarak kabul edilmiştir (31,32).…”