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




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.


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.


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).


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

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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


  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


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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.

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