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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 AbuseNational Institutes of Health
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
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)
Scientific Strategic Plan Development Action Timeline
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/
National Institute on Drug Abuse Portfolio FY 2011 Actual
Epidemiology, Services & Prevention Research -- 23%
Basic & Clinical Neuroscience & Behavioral Research -- 45%
Pharmacotherapies & Medical Consequences -- 12%
Intramural Research -- 8%
Clinical Trials Network -- 5%
RM&S -- 6%
NIDA Priority Areas
(New Targets & New Strategies)
Medical Consequences Medical Consequences
(Children & Adolescents) genetics/epigenetics development environment co-morbidity
Treatment InterventionsTreatment Interventions
Prevention ResearchPrevention Research
HIV/AIDS, HCVTeratogenic effects
Big DATA Sets Allow Analysis of Complex Systems
With sequencing costs dropping dramatically, an explosion of very large sequencing datasets is at hand, which present challenges forhigh-level data analysis and for information technology infrastructure. Creighton Exp Rev Mol Diagn 2010
• Genetics
• Epigenetics
• Proteomics
• Brain Imaging
• Clinical Data
• Systems Biology
BIG DATA: Advisory Committee to NIH Director
Data and Informatics Working Group (DIWG)(Drs. Tabak and DeMets)
Molecular Profiling
Phenotyping Imaging Grant Admin.
• 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.
ITManagement
NIDA Priority Areas
(New Targets & New Strategies)
Medical Consequences Medical Consequences
(Children & Adolescents) genetics/epigenetics development environment co-morbidity
Treatment InterventionsTreatment Interventions
Prevention ResearchPrevention Research
HIV/AIDS, HCVTeratogenic effects
METH users had higher [11C]-(+)-PHNO binding in the D3-rich midbrain (SN; +46%), globus pallidus (+9%) and ventral pallidum (+11%), and lower binding in D2-rich dorsal striatum (−4% to −12%)
Higher Binding of the Dopamine D3 Receptor-Preferring Ligand [11C]-PHNO in Methamphetamine Polydrug Users
METH >Controls
Boileau et al., J Neurosci. 2012
Buspirone (D3 receptor antagonist +)
Marketed as Buspar (Bristol Myers-Squibb 1980s) for anxiety disorders (proposed mechanism: 5HT1A receptor partial agonist)
Affinity (Ki)
5HT1A Partial Agonist 4-78 nM
D1R >10 000
D2R Partial Agonist 260nM
D3R Antagonist 3.5 nM
D4R Antagonist 78 nM
Buspirone Reduces Cocaine Self-Administration In Rhesus Monkeys
J. Bergman, N. Mello, et al. submitted
Baseline
With Buspirone0.0 20.0 40.0 60.0 80.0
0.000
0.010
0.020
0.030
0.040
0.050
0.060putamendy1 GP dy1CD dy1CB dy1putamendy2GP dy2
Time (min)
%ID
/cc
Buspirone (0.17mg/kg iv over 20 minutes) almost completely blocked D3 receptors in the monkey brain
Effects of Buspirone on [11C]PHNO (D3/D2R Ligand) Binding in the Baboon Brain
Kim et al., unpublished
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 Neurol Disord Drug Targets. 2011.
Cocaine vaccines
Shen et al., , Clin Pharm & Ther 2012; 91(1): 60-70.
Reduction in Cocaine Use in Vaccinated Patients
10 wk later cocaine 1 mg/kg iv
Nicotine Vaccine (dAd5GNE) Prevents Cocaine’sDAT Blockade in Brain
Vaccinate with dAd5GNE
No cocaine
+ Cocaine(1 MG/KG IV)
Post-vaccination
Pre-vaccination
axial
caudate
putamen
No cocaine
+ Cocaine(1MG/KG IV)
coronal sagittal
PET imaging of DAT (11C-PE2i)
Ron Crystal et al., 2012
GNC cocaine analog
EDC, S-NHS crosslinker
E1–E3–Ad5bgal
Fiber
Penton base
Hexon
Monoclonal Antibodies Against Cocaine (AAVrh.10antiCoc.Mab) in Mice
Persistence
Ser
um
an
ti-c
oca
ine
anti
bo
dy
tite
r -1
Time post-administration (wk)
Non-immunized
AAVrh.10antiCoc.Mab
101
100
102
103
104
105
240 3 5 7 9 120
102030405060708090
100
Cold cocaine competitor (mol/L)
% in
hib
itio
n
Affinity
Kd = 6.7±1.5 nM
10-9 10-710-8 10-6
Specificity
Competitor concentration (mM)
% in
hib
itio
n o
f se
rum
an
ti-c
oca
ine
anti
bo
dy
tite
r
0
20
40
60
80
100
CocaineBenzylecgonineNorcocaineEcgonine methyl esterCocaethylene
10-110-210-310-410-510-60 100
Rosenberg et al., Hum Gene Ther. 2012 April 9.
0
10
20
30
40
Co
cain
e (n
g/g
bra
in)
AAVrh.10anti-Coc.MabNon-immunized
Brain
0
20
40
60
80
100
Non-immunized AAVrh.10anti-Coc.Mab
Co
cain
e (n
g/m
l se
rum
)
Unbound
IgG bound
Total serum
Unbound
IgG bound
Total serum
Serum
Am
bu
lato
ry c
ou
nt
(cu
mu
lati
ve,
x 10
2 )Time post-administration (min)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 150
5
10
15
20
25
AAVrh.10antiCoc.Mab+ cocaine
Non-immunized+ cocaine
Non-immunized+ PBS
Locomotor Activity
Cocaine Hydrolase Encoded in Viral Vector Blocks the Reinstatement of Cocaine Seeking
in Rats for 6 Months
Reinstatement Testing following Extinction
Treatment = Single injection of either CocH vectoror control blank vector prior to extinction phase
* P < .01
# P < .01
* P < .05
Priming condition: Cocaine 10 mg/kg (2 mg/kg)
Anker JJ et al., Biol Psychiatry 2011 Dec.
Additional Reinstatement Sessions
NIDA Priority Areas
(New Targets & New Strategies)
Medical Consequences Medical Consequences
(Children & Adolescents) genetics/epigenetics development environment co-morbidity
Treatment InterventionsTreatment Interventions
Prevention ResearchPrevention Research
HIV/AIDS, HCVTeratogenic effects
2010Dr. Eric Verdin
Gladstone InstitutesNew methods to detect and
model HIV latency
2009Dr. Benjamin Chen
Mt. Sinai School of MedicineVisualizing early events of
parenteral HIV transmission (cell-cell vs. free virus)
2009Dr. Dana Gabuzda
Dana Farber Cancer Institute & Harvard Medical School
Control of T cell restoration in HIV-infected IV drug abusers
2009Dr. Jonathan Karn
Case Western Reserve UniversityDeveloping strategies for long-
term HIV suppression
2009Dr. Rafick-Pierre Sekaly
Vaccine & Gene Therapy Institute, FL
Novel pathways for purging the HIV reservoir
2008Dr. Jerome Groopman
Beth Israel Medical Center & Harvard Medical School
Blocking HIV transmission at the immune synapse
2008Dr. Julio Montaner
University of British ColumbiaHIV treatment as prevention in drug
using populations
2008Dr. Ileana Cristea
Princeton UniversityQuantifying HIV –host
interactome and regulation of gene expression
2011Dr. David Ho
Aaron Diamond AIDS Research Center
Develop a novel HIV therapy that could be administered monthly
NIDA’s Avant-Garde Award Program Is Now Open to
International Applicants
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
Westergaard RP et al., J Int AIDS Soc 2012; 15:10.
IDU HIV+ Are Much Less Likely to Receive HAART
Percentage Of Providers Who Would Defer ART By CD4+ Count
and Injection Drug Use Status
In 2010, An Estimated 22.1 Million Americans12 or Older Were Dependent On Any Illicit Drugs or Alcohol
But…Only 4.1 Million (19%) of These IndividualsHad Received Some Type ofTx In the Past Year and few involved Health Care Systems
Source: 2010 NSDUH, National Findings, SAMHSA, OAS, 2011.
Self Help Group
Outpatient Rehab
Inpatient Rehab
Outpatient Mental Health Center
Hospital Inpatient
Doctor’s Office
Emergency Room
Prison or Jail
Numbers in Millions0 .5 1.0 1.5 2.0 2.5
2.32.3
1.71.7
1.01.0
1.01.0
0.50.5
Location TX Received
Opportunities with Health Care Reform to Expand Involvement of the Health Care System
in Treatment of SUD
0.70.7
0.70.7
0.30.3
Challenge: How to Integrate Drug Abuse & AddictionScreening, 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.
Implementation of STTR in Substance Abusers
1. Health Care system (opportunities with Healthcare reform)
2. Criminal Justice system3. Substance Abuse Treatment
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.
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*0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
82.2%
18.4%
On-site testing
Off-site testing
American Journal of Public Health | April 19, 2012
0
5
10
15
20
25
30
18.3
11
16.7
2.3
25.3
8.5
23.6
10.310.9
19.7
Pooled Australia Brazil India USA
Hummeniuk R et al., Addition 2012; 107: 957-966.
Brief Intervention Control
Mean Effect Size (% Decrease) in Illicit Substance Involvement
PE
RC
EN
TScreening and Brief Intervention in
Primary Health Care Settings
Sekine et al., J Neurosci. 2008 28(22):5756-61
Microglia are activated in brains of METH abusers
Brain Imaging Studies of Microglial Activation (PET and [11C](R)-PK11195)
SIV Monkeys with encephalitis show
microglia activationVenetti et al., J Clin Invest. 2004 113(7):981-9
Kiebala et al., PLoS One. 2011 Apr 8;6(4):e18633.
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)
Ibudilast attenuates methamphetamine locomotor activity and its sensitization in mice
Snider et al., Eur J Neuroscience 2012
HIV-Infecte
d
HIV-Diagn
osed
Linked to
Care
Retained in Care
Need ART
On ART
Adherent/U
ndetectable
0
200,000
400,000
600,000
800,000
1,000,000
1,200,000
1,400,000
1,10
6,40
0
874,
056
655,
542
437,
028
349,
622
262,
217
209,
773
1,17
8,35
0
941,
950
725,
302
480,
395
426,
590
328,
475
Gardner, et al. CID 2011.
Cohen, et al. MMWR 2011
100%
80%
62%
40%32%
36%28%
79%
59%
41%
24% 19%
Major Gaps in the Implementation Cascade
• Early ART prevented linked transmission of HIV
• Unlinked transmissions were noted despite intensive couples counseling
• Early ART reduced the number of clinical events observed
HPTN 052