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