National Institute on Drug Abuse
Bringing the full power of science to bear on drug abuse and addiction
Nora D. Volkow, M.D.
Director
National Institute on Drug Abuse
Nora D. Volkow, M.D.
Director
National Institute on Drug Abuse
National Institutes of Health

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


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)


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_nisua d/add.cfm

Public Meetings

Schedule posted and updated on http://feedback.nih.gov/index.php/category/suaa/

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%

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

•
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

Data and Informatics Working Group (DIWG)
(Drs. Tabak and DeMets)
Molecular
Profiling
Phenotyping Imaging
Grant
Admin.
IT
Management
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.

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

Higher Binding of the Dopamine D
3
Receptor-
Preferring Ligand [ 11 C]-PHNO in
Methamphetamine Polydrug Users
METH >Controls
METH users had higher [ 11 C]-(+)-PHNO binding in the D
3
-rich midbrain
(SN; +46%), globus pallidus (+9%) and ventral pallidum (+11%), and lower binding in D
2
-rich dorsal striatum (−4% to −12%)
Boileau et al., J Neurosci. 2012

Marketed as Buspar (Bristol Myers-Squibb 1980s) for anxiety disorders (proposed mechanism: 5HT
1A receptor partial agonist)
Affinity
(Ki)
5HT1A Partial Agonist 4-78 nM
D1R
D2R
D3R
D4R
Partial Agonist
Antagonist
Antagonist
>10 000
260nM
3.5 nM
78 nM
Buspirone Reduces Cocaine Self-
Administration In Rhesus Monkeys
J. Bergman, N. Mello, et al. submitted

Effects of Buspirone on [
11
C]PHNO (D3/D2R Ligand)
Binding in the Baboon Brain
0,060
0,050
0,040
0,030
0,020
0,010
0,000
0,0 putamendy1
GP dy1
CD dy1
CB dy1 putamendy2
GP dy2
CD dy2
20,0 40,0 60,0
Time (min)
80,0
Buspirone (0.17mg/kg iv over 20 minutes) almost completely blocked D3 receptors in the monkey brain
Kim et al., unpublished

•
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.
Reduction in Cocaine Use in Vaccinated Patients
Fahim et al., CNS Neurol Disord Drug Targets. 2011.
Shen et al., , Clin Pharm & Ther 2012; 91(1): 60-70.

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

Monoclonal Antibodies Against Cocaine
(AAVrh.10antiCoc.Mab) in Mice
Persistence
10 5
10 4
10 3
10 2
10 1
10 0
AAVrh.10antiCoc.Mab
Non-immunized
0 3 5 7 9 12
Time post-administration (wk)
24
Affinity
100
90
80
70
60
50
40
30
20
10
0
K d
= 6.7
± 1.5 nM
10 -9 10 -8 10 -7 10 -6
Cold cocaine competitor (mol/L)
Specificity
100
80
60
40
20
0
0 10 -6 10 -5 10 -4 10 -3 10 -2 10 -1
Competitor concentration (mM)
10 0
Cocaine
Benzylecgonine
Norcocaine
Ecgonine methyl ester
Cocaethylene
40
30
20
10
0
Brain
Serum
100
80
60
40
20
Non-immunized AAVrh.10anti-Coc.Mab
0
Unbound Total
IgG bound serum
Non-immunized
Unbound Total
IgG bound serum
AAVrh.10anti-
Coc.Mab
Locomotor Activity
25
20
Non-immunized
+ cocaine
15
10
AAVrh.10antiCoc.Mab
+ cocaine
5
Non-immunized
+ PBS
0
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.

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
Treatment = Single injection of either CocH vector or control blank vector prior to extinction phase
Priming condition: Cocaine 10 mg/kg (2 mg/kg)
Anker JJ et al., Biol Psychiatry 2011 Dec.

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

2009
Dr. Benjamin Chen
Mt. Sinai School of Medicine
Visualizing early events of parenteral HIV transmission (cellcell vs. free virus)
2010
Dr. Eric Verdin
Gladstone Institutes
New methods to detect and model HIV latency
2011
Dr. David Ho
Aaron Diamond AIDS
Research Center
Develop a novel HIV therapy that could be administered monthly
2008
Dr. Ileana Cristea
Princeton University
Quantifying HIV –host interactome and regulation of gene expression
2008
Dr. Jerome Groopman
Beth Israel Medical Center &
Harvard Medical School
Blocking HIV transmission at the immune synapse
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 longterm HIV suppression
2009
Dr. Rafick-Pierre Sekaly
Vaccine & Gene Therapy
Institute, FL
Novel pathways for purging the
HIV reservoir
2008
Dr. Julio Montaner
University of British Columbia
HIV treatment as prevention in drug using populations
NIDA ’ s Avant-Garde
Award Program
Is Now Open to
International Applicants

Montaner et al., Lancet 2008
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

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.

In 2010, An Estimated
22.1 Million Americans
12 or Older Were Dependent On
Outpatient Rehab
Inpatient Rehab
Any Illicit Drugs or Alcohol
Self Help Group
Outpatient Mental
Health Center
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
Hospital Inpatient
Doctor ’ s Office
Emergency Room
Prison or Jail
Location TX Received
0.3
0.5
0.7
0.7
1.0
1.0
1.7
2.3
0 .5 1.0 1.5 2.0 2.5
Numbers in Millions
Source: 2010 NSDUH, National Findings, SAMHSA, OAS, 2011.

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

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

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.
1. Health Care system (opportunities with Healthcare reform)
2. Criminal Justice system
3. Substance Abuse Treatment

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*
90,0%
80,0%
70,0%
60,0%
50,0%
40,0%
30,0%
20,0%
10,0%
0,0%
82,2%
On-site testing
18,4%
Off-site testing
American Journal of Public Health | April 19, 2012

Mean Effect Size (% Decrease) in Illicit Substance Involvement
Pooled Australia Brazil India USA
30
25
25,3
23,6
19,7
20
18,3
16,7
15
10,9 11
10 8,5
10,3
5
0
Brief Intervention
2,3
Control
Hummeniuk R et al., Addition 2012; 107: 957-966.

11
Microglia are activated in brains of METH abusers
Sekine et al., J Neurosci. 2008 28(22):5756-61
SIV Monkeys with encephalitis show microglia activation
Venetti et al., J Clin Invest. 2004 113(7):981-9

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

Major Gaps in the Implementation Cascade
1 400 000
1 200 000
1 000 000
800 000
600 000
400 000
200 000
0
100%
79%
80%
59%
62%
40%
41%
32%
Gardner, et al. CID 2011.
Cohen, et al. MMWR 2011
24%
36%
19%
28%

•
Early ART prevented linked transmission of HIV
•
Unlinked transmissions were noted despite intensive couples counseling
•
Early ART reduced the number of clinical events observed