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ARRA Investments in the Genetics/Epigenetics of Addiction

Public Health Burden
The risk and trajectory of drug addiction is determined by multiple interacting genes and environmental factors. Furthermore, many of the genes that impact addiction risk can be directly influenced by environmental factors that can effect persistent chemical modifications (epigenetic marks) on their target genes. To alleviate the exorbitant costs (estimated to be more than $ 0.6 trillion/year) associated with drug addiction in our Nation, we must explore and better characterize these complex interactions.

Basic/Animal Research
Much of the research to identify genetic and epigenetic determinants of addiction risk is done in animals. A variety of ARRA funded grants tap into these models to identify new or verify suspected candidates:
  • Characterizing the epigenetic links between maternal care, stress sensitivity, and drug taking 1.
  • Identifying differences in gene sequence and/or expression that influence the likelihood of initiating and continuing voluntary nicotine drug-taking 2.
  • Examining the role of specific nicotine receptor variants on withdrawal and the effect of nicotine on stress and anxiety, which may uncover new targets for effective smoking cessation treatments.3,4
Technology advances: Developing Tools and Mapping Networks
New high throughput technologies are allowing researchers to amass vast quantities of information, which combined with new bioinformatics tools to analyze the data will provide critical new insights, and point to novel medication targets for addiction. Funded grants will advance the development of technologies and resources to:
  • Produce a high resolution genetic and genomic profile of a cellular response to methamphetamine 5.
  • Identify, in regions of the brain affected by drug abuse, all of the neuronal changes in gene expression and linked epigenetic marks associated with addiction 6.
  • Develop strategies to monitor epigenetic modifications in vivo that will allow investigators to study environmental effects in real time 7.
  • Search for new compounds that block the enzymes that modify the epigenome to facilitate both epigenetic research and the discovery of new classes of medications.8
  • Develop synthetic antibodies that target different epigenetic processes and components, eliminating a major bottleneck in epigenomic research 9.
Human Genetic and Genomic Studies of Risk
Studies are currently underway to examine the genetic (and epigenetic) factors contributing to a range of addictions, including critical public health problems like smoking. New approaches use emerging technologies-such as genome-wide association studies-to map and characterize inherited and drug-induced alterations in the human brain.
  • A study of candidate genes will evaluate whether and how variants of particular genes affect humans' subjective and physiological responses to nicotine administration. Knowledge obtained from this study can be used to guide future research aimed at developing individualized strategies for smoking prevention and cessation.10
  • Another candidate gene study will investigate the potential contribution of genetic variation in enzymes responsible for the breakdown of methamphetamine on the resulting cognitive impairment and brain injury in post mortem specimens .11
  • A study to characterize the ┬ádisturbances in attentional control resulting from nicotine withdrawal, including genetic influences, may lead to practical applications, such as matching of individual genetic profiles and cognitive characteristics with appropriate behavioral and pharmacotherapy smoking cessation treatments.12
ARRA funded grants are also developing or implementing new technologies to characterize and mine individual genomes and epigenomes in order to advance the goal of personalized addiction medicine and improve the effectiveness of new and existing addiction treatments.
  • One study will take advantage of genetic profiling and evaluate, for the first time, the efficacy of high-dose transdermal nicotine (vs. standard dose) among fast metabolizers of nicotine, who may require high doses to achieve therapeutic benefit.13
  • Another study screening for genetic markers that predict if someone is prone to nicotine dependence may yield information on nicotine addiction risk and help improve treatments for smoking cessation.14
Translating the results of genomic research into public health interventions and treatment programs will require the resolution of a host of ethical and policy challenges.
  • Providing policy makers with a clear understanding of the potential impact and limitations of genomic research on addictions, ensuring that research findings will integrate harmoniously into current public health measures to reduce the adverse health outcomes of addiction, and contributing to a responsible use of genetic research findings in future formulations of public health policy.15

  1. 3R21DA020117-02S1 -- Sex Differences in Vulnerability to Cocaine Addiction -- Kosten, Theresa A (contact); Nielsen, David (TX)
  2. 1RC2DA028962-01 -- Neuron-Specific Candidate Gene Expression and Adolescent Vulnerability to Smoking -- Chen, Hao; Matto, Shannon G; Sharp, Burt M (contact)(TN)
  3. 2R01DA017173-06A2 -- Stress, anxiety, and nicotine withdrawal -- De Biasi, Mariella (TX)
  4. 2R01DA014542-06A2 -- Nicotine Abuse and Memory Mechanisms -- Sumikawa, Katumi (CA)
  5. 1R01DA023690-01A2 -- High Resolution Genetic and Genomic Profiling of Methamphetamine Sensitivity -- Tarantino, Lisa M (NC)
  6. 1RC2DA028968-01 -- Translational and epigenetic profiling of cell types associated with addiction -- Heintz,Nathaniel-(NY)
  7. 1RC2DA028912-01 -- HDAC Class IIa specific PET radiotracers for PET imaging of CNS -- Gelovani, Juri (TX)
  8. 1RC1DA028790-01 -- Mechanism-based small molecule epigenetic modulators: Targeting specific HDACs -- Chen, Lin (CA)
  9. 1RC1DA028779-01 -- Renewable synthetic antibodies for epigenomics -- Koide, Shohei (IL)
  10. 1R03DA027619-01 -- Variants in nicotine receptors and pharmacogenetics -- Chen, Xiangning (VA)
  11. 1R03DA027513-01 -- Genetics of Monooxygenase Activity & Methamphetamine-Related Brain Injury in HIV -- Cherner, Mariana (CA)
  12. 1R21DA027001-01 -- Genetic Moderation of Attentional Deficits Resulting from Nicotine Withdrawal -- Evans, David (FL)
  13. 1R21DA026889-01 -- Assessment of High Dose Transdermal Nicotine for Fast Metabolizers of Nicotine -- Schnoll, Robert (PA)
  14. 1RC2DA028793-01 -- Salivary Biomarkers (DNA, RNA and Cortisol), Life Stress and Nicotine Dependence -- Andrews, Judy (OR)
  15. 2R01DA014577-05 -- KOENIG, BARBARA Translating Addiction Genomics Research into Practice: Examining Ethics & Policy (MN)

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