Basic Science Article | Published:

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

Pediatric Researchvolume 85pages398404 (2019) | Download Citation

Subjects

Abstract

Background

Whether long-term methylphenidate (MPH) results in any changes in cardiovascular function or structure can only be properly addressed through a randomized trial using an animal model which permits elevated dosing over an extended period of time.

Methods

We studied 28 male rhesus monkeys (Macaca mulatta) approximately 7 years of age that had been randomly assigned to one of three MPH dosages: vehicle control (0 mg/kg, b.i.d., n = 9), low dose (2.5 mg/kg, b.i.d., n = 9), or high dose (12.5 mg/kg, b.i.d., n = 10). Dosage groups were compared on serum cardiovascular and inflammatory biomarkers, electrocardiograms (ECGs), echocardiograms, myocardial biopsies, and clinical pathology parameters following 5 years of uninterrupted dosing.

Results

With the exception of serum myoglobin, there were no statistical differences or apparent dose–response trends in clinical pathology, cardiac inflammatory biomarkers, ECGs, echocardiograms, or myocardial biopsies. The high-dose MPH group had a lower serum myoglobin concentration (979 ng/mL) than either the low-dose group (1882 ng/mL) or the control group (2182 ng/mL). The dose response was inversely proportional to dosage (P = .0006).

Conclusions

Although the findings cannot be directly generalized to humans, chronic MPH exposure is unlikely to be associated with increased cardiovascular risk in healthy children.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Grace, C. et al. Trends of outpatient prescription drug utilization in US children, 2002–2010. Pediatrics 130, 23–31 (2012).

  2. 2.

    Nymark, T. B., Hovland, A., Bjørnstad, H. & Nielsen, E. W. A young man with acute dilated cardiomyopathy associated with methylphenidate. Vasc. Health Risk Manag. 4, 477–479 (2008).

  3. 3.

    Dadfarmay, S. & Dixon, J. A case of acute cardiomyopathy and pericarditis associated with methylphenidate. Cardiovasc. Toxicol. 9, 49–52 (2009).

  4. 4.

    Hole, L. D. & Schjott, J. Myocardial injury in a 41-year-old male treated with methylphenidate: a case report. Drug Saf. 37, 661–676 (2014).

  5. 5.

    Munk, K., Gormsen, L., Kim, W. Y. & Andersen, N. H. Cardiac arrest following a myocardial infaction in a child treated with methylphenidate. Case Rep. Pediatr. 2015, 905097 (2015).

  6. 6.

    Vetter, V. L. et al. Cardiovascular monitoring of children and adolescents with heart disease receiving medications for attention deficit/hyperactivity disorder [corrected]: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young Congenital Cardiac Defects Committee and the Council on Cardiovascular Nursing. Circulation 117, 2407–2423 (2008).

  7. 7.

    Perrin, J. M., Friedman, R. A. & Knilans, T. K., Black Box Working Group, Section on Cardiology and Cardiac Surgery. Cardiovascular monitoring and stimulant drugs for attention-deficit/hyperactivity disorder. Pediatrics 122, 451–453 (2008).

  8. 8.

    American Academy of Pediatrics/American Heart Association. American Academy of Pediatrics/American Heart Association clarification of statement on cardiovascular evaluation and monitoring of children and adolescents with heart disease receiving medications for ADHD: May 16, 2008. J. Dev. Behav. Pediatr. 29, 335 (2008).

  9. 9.

    Gould, M. S. et al. Sudden death and use of stimulant medications in youths. Am. J. Psychiatry 166, 992–1001 (2009).

  10. 10.

    Nissen, S. E. ADHD drugs and cardiovascular risk. N. Engl. J. Med. 354, 1445–1448 (2006).

  11. 11.

    Kuehn, B. M. Stimulant use linked to sudden death in children without heart problems. JAMA 302, 613–614 (2009).

  12. 12.

    Newcorn, J. H. & Donnelly, C. Cardiovascular safety of medication treatments for attention-deficity/hyperactivity disorder. Mt. Sinai J. Med. 76, 198–203 (2009).

  13. 13.

    Olfson, M. et al. Stimulants and cardiovascular events in youth with attention-deficit/hyperactivity disorder. J. Am. Acad. Child Adolesc. Psychiatry 51, 147–156 (2012).

  14. 14.

    Bange, F., Le Heuzey, M. F., Acquaviva, E., Delorme, R. & Mouren, M. C. Cardiovascular risks and management during attention deficit hyperactivity disorder treatment with methylphenidate. Arch. Pediatr. 21, 108–112 (2014).

  15. 15.

    Shin, J. Y., Roughead, E. E., Park, B. J. & Pratt, N. L. Cardiovascular safety of methylphenidate among children and young people with attention-deficit/hyperactivity disorder (ADHD): nationwide self controlled case series. BMJ 353, i2550 (2016).

  16. 16.

    Hennissen, L. et al. Cardiovascular effects of stimulant and non-stimulant medication for children and adolescents with ADHD: a systematic review and meta-analysis of trials of methylphenidate, amphetamines and atomoxetine. CNS Drugs 31, 199–215 (2017).

  17. 17.

    Subcommittee on Attention-Deficit/Hyperactivity Disorder; Steering Committee on Quality Improvement and Management, Wolraich, M. et al. ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics 128, 1007–1022 (2011).

  18. 18.

    Take, G. et al. Dose-dependent immunohistochemical and ultrastructural changes after oral methylphenidate administration in rat heart tissue. Anat. Histol. Embryol. 37, 303–308 (2008).

  19. 19.

    Henderson, T. A. & Fischer, V. W. Effects of methylphenidate (Ritalin) on mammalian myocardial ultrastructure. Am. J. Cardiovasc. Pathol. 5, 68–78 (1995).

  20. 20.

    Witt, K. L. et al. No increases in biomarkers of genetic damage or pathological changes in heart and brain tissue in male rats administered methylphenidate hydrochloride (Ritalin) for 28 days. Environ. Mol. Mutagen. 51, 80–88 (2010).

  21. 21.

    Zhang, X. et al. MicroPet/CT assessment of FDG uptake in brain after long-term methylphenidate treatment in nonhuman primates. Neurotoxicol. Teratol. 56, 68–74 (2016).

  22. 22.

    Morris, S. M. et al. The genetic toxicology of methylphenidate hydrochloride in non-human primates. Mutat. Res. 673, 59–65 (2009).

  23. 23.

    Mattison, D. R. et al. Pubertal delay in male nonhuman primates (Macaca mulatta) treated with methylphenidate. Proc. Natl Acad. Sci. USA 108, 16301–16306 (2011).

  24. 24.

    Rodriguez, J. S. et al. The effects of chronic methylphenidate administration on operant test battery performance in juvenile rhesus monkeys. Neurotoxicol. Teratol. 32, 142–151 (2010).

  25. 25.

    Yang, X. et al. Development of a physiologically based model to describe the pharmacokinetics of methylphenidate in juvenile and adult humans and nonhuman primates. PLoS ONE 9, e106101 (2014).

  26. 26.

    Matsuzawa, T. & Nagai, Y. Comparative haematological and plasma chemistry values in purpose-bred squirrel, cynomolgus and rhesus monkeys. Comp. Haematol. Int 4, 43–48 (1994).

  27. 27.

    https://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/35110. Accessed 25 Feb 2018.

  28. 28.

    Sallach, S. M. et al. Change in serum myoglobin to detect acute myocardial infarction in patients with normal troponin I levels. Am. J. Cardiol. 94, 864–867 (2004).

  29. 29.

    Keltz, E., Fahmi, Y., Khan, Y. & Mann, G. Rhabdomyolysis. The role of diagnostic and prognostic factors. Muscles Liga. Tendons J. 3, 303–312 (2013).

  30. 30.

    Olerud, J. E., Homer, L. D. & Carroll, H. W. Incidence of acute exertional rhabdomyolysis: serum myoglobin and enzyme levels as indicators of muscle injury. Arch. Intern. Med. 136, 692–697 (1976).

  31. 31.

    Reuter, J. D., Dysko, R. E. & Crisp, C. E. Review of exertional rhabdomyolysis in a rhesus monkey (Macaca mulatta). J. Med. Primatol. 27, 303–309 (1998).

  32. 32.

    Findling, R. L. et al. Short- and long-term cardiovascular effects of mixed amphetamine salts extended release in children. J. Pediatr. 147, 348–354 (2005).

  33. 33.

    Donner, R., Michaels, M. A. & Ambrosini, P. J. Cardiovascular effects of mixed amphetamine salts extended release in the treatment of school-aged children with attention-deficit/hyperactivity disorder. Biol. Psychiatry 61, 706–712 (2007).

  34. 34.

    Wilens, T. E., Biederman, J. & Lerner, M. Effects of once-daily osmotic release methylphenidate on blood pressure and heart rate in children with attention-deficit/hyperactivity disorder: results from a one-year follow-up study. J. Clin. Psychopharmacol. 24, 36–41 (2004).

  35. 35.

    Wilens, T. E., Spencer, T. J. & Biederman, J. Short- and long-term cardiovascular effects of mixed amphetamine salts extended-release in adolescents with ADHD. CNS Spectr. 10(Suppl. 15), 22–30 (2005).

  36. 36.

    Biederman, J. et al. A randomized, placebo-controlled trial of OROS methyphenidate in adults with attention-deficit disorder. Biol. Psychiatry 59, 829–835 (2006).

  37. 37.

    Schelleman, H. et al. Methylphenidate and risk of serious cardiovascular events in adults. Am. J. Psychiatry 169, 178–185 (2012).

  38. 38.

    Schelleman, H. et al. Cardiovascular events and death in children exposed and unexposed to ADHD agents. Pediatrics 127, 1102–1110 (2011).

  39. 39.

    Habel, L. A. et al. ADHD drugs and serious cardiovascular events in children and young adults. JAMA 365, 1896–1904 (2011).

  40. 40.

    Lipshultz, S. E., Cohen, H., Colan, S. D. & Herman, E. H. The relevance of information generated by in vitro experimental models to clinical doxorubicin cardiotoxicity. Leuk. Lymphoma 47, 1454–1458 (2006).

Download references

Acknowledgments

Andrea Parra and Katherine Kralievits provided support for the data collection and database development for this study. This study was funded by awards from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the NCTR, and the FDA. NCTR ID #: E0728711. The opinions and conclusions are those of the authors and not necessarily of the FDA.

Author information

Affiliations

  1. Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA

    • James D. Wilkinson
  2. Animal Resource Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    • Ralph Callicott
  3. Toxicology and Formulations, Pro Natural Brands, LLC, Victor, NY, 14564, USA

    • William F. Salminen
  4. Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, 33156, USA

    • Satinder K. Sandhu
    •  & Paolo G. Rusconi
  5. Division of Systems Biology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, 72079, USA

    • James Greenhaw
  6. Office of Scientific Coordination, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, 72079, USA

    • Angel Paredes
    •  & Yvonne Jones
  7. Toxicologic Pathology Associates, Jefferson, AR, 72079, USA

    • Kelly Davis
  8. Division of Neurotoxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, 72079, USA

    • Merle G. Paule
  9. Office of the Center Director, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, 72079, USA

    • William Slikker Jr.
  10. Department of Pediatrics, Wayne State University School of Medicine and Children’s Hospital of Michigan, Detroit, MI, 48201, USA

    • Jason Czachor
    • , Amy Bodien
    •  & Joslyn A. Westphal
  11. Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, 33156, USA

    • Danielle D. Dauphin
  12. Department of Pediatrics, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Oishei Children’s Hospital, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14203, USA

    • Steven E. Lipshultz

Authors

  1. Search for James D. Wilkinson in:

  2. Search for Ralph Callicott in:

  3. Search for William F. Salminen in:

  4. Search for Satinder K. Sandhu in:

  5. Search for James Greenhaw in:

  6. Search for Angel Paredes in:

  7. Search for Kelly Davis in:

  8. Search for Yvonne Jones in:

  9. Search for Merle G. Paule in:

  10. Search for William Slikker Jr. in:

  11. Search for Paolo G. Rusconi in:

  12. Search for Jason Czachor in:

  13. Search for Amy Bodien in:

  14. Search for Joslyn A. Westphal in:

  15. Search for Danielle D. Dauphin in:

  16. Search for Steven E. Lipshultz in:

Contributions

Substantial contributions to conception and design: J.D.W., S.E.L., R.C., W.F.S., W.S. Acquisition of data: J.D.W., R.C., S.K.S., J.G., A.P., K.D., Y.J., D.D.D. Analysis and interpretation of data: All authors. Drafting the article: J.D.W., R.C., W.F.S., S.K.S., A.P., K.D., P.G.R., J.C., A.B., J.A.W., S.E.L. Revising it critically for important intellectual content: All authors. Final approval of the version to be published: All authors.

Competing interests

The authors declare no competing interest.

Corresponding author

Correspondence to Steven E. Lipshultz.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/s41390-018-0256-9