The increased use of amphetamine-type stimulants (ATS), which refer to the group of stimulants including methamphetamine (MA) and amphetamine, has become a major global health problem in recent years. There is also an increasing concern about the high rate of the non-medical use of prescription stimulants among adolescents. In this competing renewal of DA024070, an international collaborative study aimed to determine the effects of MA on the developing brain, we propose to extend our studies in ATS-using adolescents to evaluate a novel treatment strategy for this population. On the basis of preliminary findings identifying adolescent-specific brain and cognitive vulnerability to stimulant exposure and the neuroprotective properties of cytidine-5'-diphosphate choline (CDP-choline), we propose to conduct a 12-week, randomized, double-blind, placebo-controlled trial of CDP-choline in ATS-using adolescents. As outcome measures, multi-level assessments will be performed at molecular, neural circuitry, cognitive, and clinical levels. It will be determined whether CDP-choline administration, compared to placebo administration, will 1) repair ATS-induced neural cell damage within the target brain regions, which will be assessed using multinuclear magnetic resonance spectroscopic imaging, 2) improve cognitive deficits and normalize the relevant target neural circuits, which will be assessed using neuropsychological tests and multimodal imaging analyses including cortical thickness analysis, diffusion tensor imaging analysis, and network analysis, and 3) reduce ATS-taking behaviors, which will be assessed using a combination of urine monitoring and self-report of ATS use. This study will demonstrate that CDP-choline engages the treatment target and thereby provides clinical benefits to ATS-using adolescents. In the context of the unique opportunity to recruit a special population, such as ATS-using adolescents, in Seoul, South Korea, this project will be performed based on the international collaboration between Perry F. Renshaw at the Brain Institute, the University of Utah, UT, USA and In Kyoon Lyoo at the Ewha Brain Institute, Ewha W. University, Seoul, South Korea. We believe that this research proposal is highly responsive to the International Research Collaboration on Drug Abuse and Addiction Research Program Announcement (PA-12- 040) that encourages the utilization of unique resources or subject populations which would otherwise be difficult to access domestically. As is also acknowledged in the '2007 Distinguished International Scientist Collaboration Award' and '2008 International Program Award for Excellence [Collaborative Research]', our well established collaboration will contribute to the success of this proposal.

Public Health Relevance

Given the high rates of amphetamine type stimulant (ATS) use among adolescents, along with the lack of effective therapeutic strategies for this population, there is an urgent need for clinical trials of novel, target- engaged medications in ATS-using adolescents. This project proposes to assess the efficacy of cytidine-5'- diphosphate choline (CDP-choline) in treating brain, cognitive, and behavioral abnormalities related to ATS use in adolescents using multimodal neuroimaging, neuropsychological tests, and a combination of urine monitoring and self-report of ATS use.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Child Psychopathology and Developmental Disabilities Study Section (CPDD)
Program Officer
Sirocco, Karen
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Utah
Schools of Medicine
Salt Lake City
United States
Zip Code
Kim, Jieun E; Kim, Geon Ha; Hwang, Jaeuk et al. (2018) Metabolic alterations in the anterior cingulate cortex and related cognitive deficits in late adolescent methamphetamine users. Addict Biol 23:327-336
Ma, Jiyoung; Kang, Hee Jin; Kim, Jung Yoon et al. (2017) Network attributes underlying intellectual giftedness in the developing brain. Sci Rep 7:11321
Lyoo, I K; Yoon, S; Kim, T S et al. (2015) Predisposition to and effects of methamphetamine use on the adolescent brain. Mol Psychiatry 20:1516-24
Hwang, Jaeuk; Kim, Jieun E; Kaufman, Marc J et al. (2013) Enlarged cavum septum pellucidum as a neurodevelopmental marker in adolescent-onset opiate dependence. PLoS One 8:e78590
Lyoo, In Kyoon; Yoon, Sujung; Kim, Tae-Suk et al. (2012) A randomized, double-blind placebo-controlled trial of oral creatine monohydrate augmentation for enhanced response to a selective serotonin reuptake inhibitor in women with major depressive disorder. Am J Psychiatry 169:937-945
Yoon, Sujung J; Lyoo, In Kyoon; Kim, Hengjun J et al. (2010) Neurochemical alterations in methamphetamine-dependent patients treated with cytidine-5'-diphosphate choline: a longitudinal proton magnetic resonance spectroscopy study. Neuropsychopharmacology 35:1165-73
Haws, Charlotte A; Gray, Douglas D; Yurgelun-Todd, Deborah A et al. (2009) The possible effect of altitude on regional variation in suicide rates. Med Hypotheses 73:587-90