Drug Abuse & Addiction Research: Progress, Priorities, and Opportunities at NIDA

1. National Institute on Drug AbuseBringing the full power of science to bear on drug abuse and addictionNora D. Volkow, M.D.DirectorNational Institute on Drug Abuse Drug Abuse & Addiction Research: Progress, Priorities, and Opportunities at NIDA Nora D. Volkow, M.D. Director National Institute on Drug Abuse National Institutes of Health

2. Strategy for Development of Scientific Strategic Plan for New SUD Institute • Identify scientific and public health needs not addressed by NIH • input from NIH scientific staff • input from external stakeholders (researchers, advocates) • Assess suggested scientific opportunities and public health needs, in light of missions of NIDA, NIAAA, NCI & other ICs • Develop a draft scientific strategic plan • Integrate new scientific opportunities identified by NIH & the public with existing priorities in SUD research • Solicit public input on draft plan

3. Scientific Strategic Plan Development Action Timeline • June 2011 - Fall 2012: input from stakeholders • February 2012: RFI published • Spring 2012: Conduct virtual meetings • Spring/Summer 2012: Conduct town hall meetings and teleconferences with stakeholders • Fall 2012: Release of Draft Scientific Strategic Plan and • public comment period • December 2012: Final Recommendations to NIH Director • January/February 2013: Include President’s FY 2014 Budget • Begin implementing Scientific Strategic Plan that is not dependent on • reorganization • October 2013: National Institute of Substance Use and • Addiction Disorders (NISUAD)

4. Solicitation for Public Stakeholder Input • Request for Information • February 8, 2012 • Closing date: May 11, 2012 • How to Submit a Response : All comments must be submitted electronically to: http://grants.nih.gov/grants/guide/rfi_files/nih_nisuad/add.cfm • Public Meetings • Schedule posted and updated on http://feedback.nih.gov/index.php/category/suaa/

5. National Institute on Drug Abuse Portfolio FY 2011 Actual Basic & Clinical Neuroscience & Behavioral Research -- 45% Epidemiology, Services & Prevention Research -- 23% Pharmacotherapies & Medical Consequences -- 12% Clinical Trials Network -- 5% Intramural Research -- 8% RM&S -- 6%

6. NIDA Priority Areas Prevention Research (Children & Adolescents) genetics/epigenetics development environment co-morbidity Treatment Interventions (New Targets & New Strategies) Medical Consequences HIV/AIDS, HCV Teratogenic effects

7. Genetics • Epigenetics • Proteomics • Brain Imaging • Clinical Data • Systems Biology With sequencing costs dropping dramatically, an explosion of very large sequencing datasets is at hand, which present challenges for high-level data analysis and for information technology infrastructure. Creighton Exp Rev Mol Diagn 2010 Big DATA Sets Allow Analysis of Complex Systems

8. BIG DATA: Advisory Committee to NIH Director Data and Informatics Working Group (DIWG) (Drs. Tabak and DeMets) Grant Admin. Molecular Profiling IT Management Imaging Phenotyping • The first three subgroups will provide information to the DIWG • on policies and investments needed to facilitate data sharing and • integration. • The DIWG will develop recommendations to present to the ACD • and the NIH Director on policies regarding the management, • integration and analysis of research data and administrative data.

9. NIDA Priority Areas Prevention Research (Children & Adolescents) genetics/epigenetics development environment co-morbidity Treatment Interventions (New Targets & New Strategies) Medical Consequences HIV/AIDS, HCV Teratogenic effects

10. Higher Binding of the Dopamine D3 Receptor-Preferring Ligand [11C]-PHNO in Methamphetamine Polydrug Users METH >Controls METH users had higher [11C]-(+)-PHNO binding in the D3-rich midbrain (SN; +46%), globuspallidus (+9%) and ventral pallidum (+11%), and lower binding in D2-rich dorsal striatum (−4% to −12%) Boileau et al., J Neurosci. 2012

11. Buspirone (D3 receptor antagonist +) Marketed as Buspar (Bristol Myers-Squibb 1980s) for anxiety disorders (proposed mechanism: 5HT1A receptor partial agonist) Buspirone Reduces Cocaine Self-Administration In Rhesus Monkeys J. Bergman, N. Mello, et al. submitted

12. Effects of Buspirone on [11C]PHNO (D3/D2R Ligand) Binding in the Baboon Brain Buspirone (0.17mg/kg iv over 20 minutes) almost completely blocked D3 receptors in the monkey brain Baseline With Buspirone Kim et al., unpublished

13. Nicotine vaccines • NicVAX, failed to meet primary endpoint in two phase III studies • Higher abstinence was observed in subjects with higher immunity to nicotine. Strategies: • novel carriers and/or adjuvants for higher immunogenicity • targeting subjects with robust responses • Combining with medications. Fahim et al., CNS NeurolDisord Drug Targets. 2011. Cocaine vaccines Reduction in Cocaine Use in Vaccinated Patients Shen et al., , Clin Pharm & Ther 2012; 91(1): 60-70.

14. Nicotine Vaccine (dAd5GNE) Prevents Cocaine’s DAT Blockade in Brain GNC cocaine analog E1–E3–Ad5bgal PET imaging of DAT (11C-PE2i) Fiber Pre-vaccination Penton base Hexon No cocaine EDC, S-NHS crosslinker + Cocaine (1 MG/KG IV) • Vaccinate with dAd5GNE axial sagittal coronal Post-vaccination caudate No cocaine putamen 10 wk later cocaine 1 mg/kg iv + Cocaine (1MG/KG IV) Ron Crystal et al., 2012

15. Monoclonal Antibodies Against Cocaine (AAVrh.10antiCoc.Mab) in Mice Affinity Persistence 105 100 90 104 80 AAVrh.10antiCoc.Mab 70 103 Serum anti-cocaine antibody titer -1 60 % inhibition 50 102 40 101 30 Non-immunized 20 Kd = 6.7±1.5 nM 100 10 0 10-9 10-8 10-7 10-6 0 3 5 7 9 12 24 Time post-administration (wk) Cold cocaine competitor (mol/L) Specificity Serum 100 Brain Locomotor Activity 80 Cocaine 100 40 60 Benzylecgonine % inhibition of serum anti-cocaine antibody titer Norcocaine 40 80 25 Ecgonine methyl ester 30 Cocaethylene 20 60 20 0 Non-immunized + cocaine Cocaine (ng/g brain) Cocaine (ng/ml serum) 20 10-6 10-5 10-4 10-3 10-2 10-1 100 0 40 15 Competitor concentration (mM) Ambulatory count (cumulative, x 102) 10 20 AAVrh.10antiCoc.Mab + cocaine 10 0 0 Unbound Total serum Unbound Total serum AAVrh.10anti-Coc.Mab Non-immunized 5 Non-immunized + PBS IgG bound IgG bound 0 Non-immunized AAVrh.10anti-Coc.Mab 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time post-administration (min) Rosenberg et al., Hum Gene Ther. 2012 April 9.

16. Cocaine Hydrolase Encoded in Viral Vector Blocks the Reinstatement of Cocaine Seeking in Rats for 6 Months Reinstatement Testing following Extinction Additional Reinstatement Sessions #P < .01 *P < .05 *P < .01 Priming condition: Cocaine 10 mg/kg (2 mg/kg) Treatment = Single injection of either CocH vector or control blank vector prior to extinction phase Anker JJ et al., Biol Psychiatry 2011 Dec.

17. NIDA Priority Areas Prevention Research (Children & Adolescents) genetics/epigenetics development environment co-morbidity Treatment Interventions (New Targets & New Strategies) Medical Consequences HIV/AIDS, HCV Teratogenic effects

18. 2009 Dr. Benjamin Chen Mt. Sinai School of Medicine Visualizing early events of parenteral HIV transmission (cell-cell vs. free virus) 2009 Dr. Dana Gabuzda Dana Farber Cancer Institute & Harvard Medical School Control of T cell restoration in HIV-infected IV drug abusers 2009 Dr. Jonathan Karn Case Western Reserve University Developing strategies for long-term HIV suppression 2010 Dr. Eric Verdin Gladstone Institutes New methods to detect and model HIV latency 2009 Dr. Rafick-Pierre Sekaly Vaccine & Gene Therapy Institute, FL Novel pathways for purging the HIV reservoir 2011 Dr. David Ho Aaron Diamond AIDS Research Center Develop a novel HIV therapy that could be administered monthly 2008 Dr. Julio Montaner University of British Columbia HIV treatment as prevention in drug using populations 2008 Dr. Ileana Cristea Princeton University Quantifying HIV –host interactome and regulation of gene expression NIDA’s Avant-Garde Award Program Is Now Open to International Applicants 2008 Dr. Jerome Groopman Beth Israel Medical Center & Harvard Medical School Blocking HIV transmission at the immune synapse

19. HAART as HIV Prevention Decline in Community Viral Load is Strongly Associated with Declining HIV Incidence among IDUs (ALIVE) GD Kirk, N Galai1, J Astemborski, B Linas, D Celentano, SH Mehta, D Vlahov Montaner et al., Lancet 2008

20. IDU HIV+ Are Much Less Likely to Receive HAART Percentage Of Providers Who Would Defer ART By CD4+ Count and Injection Drug Use Status Westergaard RP et al., J Int AIDS Soc 2012; 15:10.

21. Opportunities with Health Care Reform to Expand Involvement of the Health Care System in Treatment of SUD Location TX Received In 2010, An Estimated 22.1 Million Americans 12 or Older Were Dependent On Any Illicit Drugs or Alcohol But…Only 4.1 Million (19%) of These Individuals Had Received Some Type of Tx In the Past Year and few involved Health Care Systems 2.3 Self Help Group Outpatient Rehab Inpatient Rehab Outpatient Mental Health Center Hospital Inpatient Doctor’s Office Emergency Room Prison or Jail 1.7 1.0 1.0 0.7 0.7 0.5 0.3 0 .5 1.0 1.5 2.0 2.5 Numbers in Millions Source: 2010 NSDUH, National Findings, SAMHSA, OAS, 2011.

22. Challenge: How to Integrate Drug Abuse & Addiction Screening, Prevention & Treatment into the Healthcare System

23. Hierarchical Genetic Organization of Human Cortical Surface Area (406 twins) Chen CH et al., Science 2012 March 30; 335( 6076): 1634-1636.

24. Despite increases in ART incidence of HIV in USA has remained stable at ∼56,300 new infections per year. This is likely to reflect in part failure to treat those with SUD. Of the 1.1 M individuals living with HIV in the US, 21% are estimated to be unaware of their HIV infection.Undetected cases are likely to be higher among individuals with SUD. Implementation of STTR in Substance Abusers Health Care system (opportunities with Healthcare reform) Criminal Justice system Substance Abuse Treatment

25. Implementing Rapid HIV Testing With or Without Counseling in Drug Tx Centers • Combined on-site rapid testing participants received more HIV results (82.2%) than off-site testing referral participants (18.4%) • p < 0.001, aRR 4.52, 97.5% CI (3.57, 5.72) • *No effect of counseling* On-site testing Off-site testing CTN-0032 American Journal of Public Health | April 19, 2012

26. Screening and Brief Intervention in Primary Health Care Settings Mean Effect Size (% Decrease) in Illicit Substance Involvement PERCENT Control Brief Intervention Hummeniuk R et al., Addition 2012; 107: 957-966.

27. Brain Imaging Studies of Microglial Activation (PET and [11C](R)-PK11195) Microglia are activated in brains of METH abusers SIV Monkeys with encephalitis show microglia activation Sekine et al., J Neurosci. 2008 28(22):5756-61 Venetti et al., J Clin Invest. 2004 113(7):981-9

28. Ibudilast (cyclic AMP PDE inhibitor; anti-asthma drug) • Antinflammatory effects (attenuate glial cell activation; inhibits • chemokine production; increases IL-10 production) • Clinical trials testing it in MS, opioid withdrawal, and neuropathic pain. • Prevents HIV-1 Tat-mediated activation of microglial cells (tx HAND) Kiebala et al., PLoS One. 2011 Apr 8;6(4):e18633. Ibudilast attenuates methamphetamine locomotor activity and its sensitization in mice Snider et al., Eur J Neuroscience 2012

29. Major Gaps in the Implementation Cascade

30. HPTN 052 • Early ART prevented linked • transmission of HIV • Unlinked transmissions were noted • despite intensivecouples counseling • Early ART reduced the number of • clinical events observed