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

Overview

Journal Environ Mol Mutagen

Specialties Environmental Health
Molecular Biology

Date 2009 Jul 28

PMID 19634155

Citations 6

Authors

Kristine L Witt

David E Malarkey

Cheryl A Hobbs

Jeffrey P Davis

Grace E Kissling

William Caspary

Gregory Travlos

Leslie Recio

Affiliations

Soon will be listed here.

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]: Prog Neuropsychopharmacol Biol Psychiatry 31:1282-1288) 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.

Citing Articles

Behavioral, Neurochemical and Developmental Effects of Chronic Oral Methylphenidate: A Review.

Senior D, Ahmed R, Arnavut E, Carvalho A, Lee W, Blum K J Pers Med. 2023; 13(4).

PMID: 37108960 PMC: 10144804. DOI: 10.3390/jpm13040574.

Neuroprotective Properties of Minocycline Against Methylphenidate-Induced Neurodegeneration: Possible Role of CREB/BDNF and Akt/GSK3 Signaling Pathways in Rat Hippocampus.

Motaghinejad M, Motevalian M Neurotox Res. 2022; 40(3):689-713.

PMID: 35446003 DOI: 10.1007/s12640-021-00454-7.

Evaluation of 2-methoxy-4-nitroaniline (MNA) in hypersensitivity, 14-day subacute, reproductive, and genotoxicity studies.

Frawley R, Witt K, Cunny H, Germolec D, Jackson-Humbles D, Malarkey D Toxicology. 2020; 441:152474.

PMID: 32380031 PMC: 7717523. DOI: 10.1016/j.tox.2020.152474.

A randomized controlled laboratory study on the long-term effects of methylphenidate on cardiovascular function and structure in rhesus monkeys.

Wilkinson J, Callicott R, Salminen W, Sandhu S, Greenhaw J, Paredes A Pediatr Res. 2018; 85(3):398-404.

PMID: 30555154 PMC: 6779032. DOI: 10.1038/s41390-018-0256-9.

Assessment of potential cardiovascular risks of methylphenidate in comparison with sibutramine: do we need a SCOUT (trial)?.

Antel J, Albayrak O, Heusch G, Banaschewski T, Hebebrand J Eur Arch Psychiatry Clin Neurosci. 2014; 265(3):233-47.

PMID: 25149468 DOI: 10.1007/s00406-014-0522-8.

References

Walitza S, Kampf K, Artamonov N, Romanos M, Gnana Oli R, Wirth S . No elevated genomic damage in children and adolescents with attention deficit/hyperactivity disorder after methylphenidate therapy. Toxicol Lett. 2008; 184(1):38-43. DOI: 10.1016/j.toxlet.2008.10.011. View

Williams D . The comparison of several dose levels with a zero dose control. Biometrics. 1972; 28(2):519-31. View

Torous D, Dertinger S, Hall N, Tometsko C . Enumeration of micronucleated reticulocytes in rat peripheral blood: a flow cytometric study. Mutat Res. 2000; 465(1-2):91-9. DOI: 10.1016/s1383-5718(99)00216-8. View

Biederman J, Spencer T, Wilens T, Prince J, Faraone S . Treatment of ADHD with stimulant medications: response to Nissen perspective in the New England Journal of Medicine. J Am Acad Child Adolesc Psychiatry. 2006; 45(10):1147-1150. DOI: 10.1097/01.chi.0000227883.88521.e6. View

Witt K, Livanos E, Kissling G, Torous D, Caspary W, Tice R . Comparison of flow cytometry- and microscopy-based methods for measuring micronucleated reticulocyte frequencies in rodents treated with nongenotoxic and genotoxic chemicals. Mutat Res. 2007; 649(1-2):101-13. PMC: 2234598. DOI: 10.1016/j.mrgentox.2007.08.004. View

Witt K, Shelby M, Itchon-Ramos N, Faircloth M, Kissling G, Chrisman A . Methylphenidate and amphetamine do not induce cytogenetic damage in lymphocytes of children with ADHD. J Am Acad Child Adolesc Psychiatry. 2008; 47(12):1375-83. PMC: 2807376. DOI: 10.1097/CHI.0b013e3181893620. View

Safer D . Are stimulants overprescribed for youths with ADHD?. Ann Clin Psychiatry. 2000; 12(1):55-62. DOI: 10.1023/a:1009031211900. View

Devilbiss D, Berridge C . Cognition-enhancing doses of methylphenidate preferentially increase prefrontal cortex neuronal responsiveness. Biol Psychiatry. 2008; 64(7):626-35. PMC: 2603602. DOI: 10.1016/j.biopsych.2008.04.037. View

Gray J, Punsoni M, Tabori N, Melton J, Fanslow V, Ward M . Methylphenidate administration to juvenile rats alters brain areas involved in cognition, motivated behaviors, appetite, and stress. J Neurosci. 2007; 27(27):7196-207. PMC: 6794586. DOI: 10.1523/JNEUROSCI.0109-07.2007. View

10.

MacGregor J, Bishop M, McNamee J, Hayashi M, Asano N, Wakata A . Flow cytometric analysis of micronuclei in peripheral blood reticulocytes: II. An efficient method of monitoring chromosomal damage in the rat. Toxicol Sci. 2006; 94(1):92-107. DOI: 10.1093/toxsci/kfl076. View

11.

Dommett E, Henderson E, Westwell M, Greenfield S . Methylphenidate amplifies long-term plasticity in the hippocampus via noradrenergic mechanisms. Learn Mem. 2008; 15(8):580-6. DOI: 10.1101/lm.1092608. View

12.

Andreazza A, Frey B, Valvassori S, Zanotto C, Gomes K, Comim C . DNA damage in rats after treatment with methylphenidate. Prog Neuropsychopharmacol Biol Psychiatry. 2007; 31(6):1282-8. DOI: 10.1016/j.pnpbp.2007.05.012. View

13.

Walitza S, Werner B, Romanos M, Warnke A, Gerlach M, Stopper H . Does methylphenidate cause a cytogenetic effect in children with attention deficit hyperactivity disorder?. Environ Health Perspect. 2007; 115(6):936-40. PMC: 1892117. DOI: 10.1289/ehp.9866. View

14.

Williams D . A test for differences between treatment means when several dose levels are compared with a zero dose control. Biometrics. 1971; 27(1):103-17. View

15.

Mortelmans K, Haworth S, Lawlor T, Speck W, Tainer B, Zeiger E . Salmonella mutagenicity tests: II. Results from the testing of 270 chemicals. Environ Mutagen. 1986; 8 Suppl 7:1-119. View

16.

Manjanatha M, Shelton S, Dobrovolsky V, Shaddock J, McGarrity L, Doerge D . Pharmacokinetics, dose-range, and mutagenicity studies of methylphenidate hydrochloride in B6C3F1 mice. Environ Mol Mutagen. 2008; 49(8):585-93. DOI: 10.1002/em.20407. View

17.

Tucker J, Suter W, Petibone D, Thomas R, Bailey N, Zhou Y . Cytogenetic assessment of methylphenidate treatment in pediatric patients treated for attention deficit hyperactivity disorder. Mutat Res. 2009; 677(1-2):53-8. DOI: 10.1016/j.mrgentox.2009.05.005. View

18.

Morris S, Dobrovolsky V, Shaddock J, Mittelstaedt R, Bishop M, Manjanatha M . The genetic toxicology of methylphenidate hydrochloride in non-human primates. Mutat Res. 2009; 673(1):59-66. DOI: 10.1016/j.mrgentox.2008.12.001. View

19.

Burlinson B, Tice R, Speit G, Agurell E, Brendler-Schwaab S, Collins A . Fourth International Workgroup on Genotoxicity testing: results of the in vivo Comet assay workgroup. Mutat Res. 2006; 627(1):31-5. DOI: 10.1016/j.mrgentox.2006.08.011. View

20.

Zito J, Safer D, dosReis S, GARDNER J, Boles M, Lynch F . Trends in the prescribing of psychotropic medications to preschoolers. JAMA. 2000; 283(8):1025-30. DOI: 10.1001/jama.283.8.1025. View