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

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

Addiction and its Treatment

Nora D. Volkow, M.D.Director

@NIDAnews

National Instituteon Drug Abuse

Nestler, Nature Neurosci, 2005.

`

Time After Methamphetamine

Dop

amin

e (n

M)

METHAMPHETAMINE2000

1500

1000

500

0

512.5

Dose (mg/kg IV)

0 20 40 60 80min

100

150

200

DA

Con

cent

ratio

n )

SEX

50

01 2 3 4 5 6 7 8 9 1011 1213 1415 1617

Drugs and Natural Rewards ACTIVATE Dopamine in Reward Regions

TYROSINE

DA

DOPA

DA

DA

DA

DA

TYROSINE

DA

DOPA

DA

DA

DA

D AD A D A D A

D AD AD A

RRRRRR

DA & the Rewarding Effects of Drugs in Humans

racloprideraclopride

DA DA

-10 0 10 20 30 40-202468

10

Hig

h(0

-10)

Intravenous MPH(1 min)

Volkow et al., JPET 291:409-415, 1999.

0

24

6

8

10

Change in DA(% change Bmax/Kd)

Hig

h(0

-10)

0` 10 20 30 40 50

Oral MPH(60 minutes)

DA increases induced by intravenous but not by oral administration of MPH were associated with the “high”. WHY?

methylphenidate

TYROSINE

DA

DOPA

DA

DA

DA

DA

TYROSINE

DA

DOPA

DA

DA

DA

DADA DA DA

DADADA

RRRRRR

-10 0 10 20 30 40-202468

10

Self-

Repo

rts

(0-1

0)

Change in DopamineBmax/kd (Placebo - MP)

“High”

Reward Circuit in Addiction

racloprideraclopride

DA DA

Volkow et al., JPET 291(1):409-415, 1999.

NAcc VPREWARD

methylphenidate

Normal Control

Cocaine Abuser

Placebo MP

05

101520253035

% C

hang

e B

max

/Kd

Controls(n = 20)

Abusers(n = 20)

P < 0.003

21%

9%

Volkow et al., Nature 1997.

Effects of MP (0.5mg/kg iv) in Striatal DA in Cocaine Abusers

Volkow et al., PNAS 2011.

Cocaine abusers

Controls

Placebo MP

0

5

10

15

20

25

Controls(n=17)

Abusers(n=17)%

Cha

nge

Bm

ax/K

d3%

14%

P < 0.001

DETOXIFIED ACTIVE USERS

2

13%

Control subjects

Cocaine abusers with CUE

Cocaine abusers with NEUTRAL

MP-Induced DA Change Controls vs Cocaine Abusers (with and without cues)

P <0.001

MP increased DA in controls (p<0.001) whereas in cocaine abusers the effects were minimal and only significant in VS (p<0.05)

P <0.05

P <0.05

Volk

ow e

t al M

olPs

ychi

atry

201

4

Controls CocaineAbusers

In cocaine abusers MP-induced DA increases in VS, while very blunted, triggered craving

Volkow et al Mol Psychiatry 2014

DA

DA

DA

DADA DADA

DA

signal

Motivation & ExecutiveControl Circuits ACG

OFCSCCINHIBITORY CONTROL

EXECUTIVEFUNCTION

PFC

MOTIVATION/DRIVE

Here we tested if, in addictedsubjects, changes in DA function were linked withdisruption of frontal activity asassessed by multiple tracerstudies that evaluated in thesame subject dopamine D2receptors and brain glucosemetabolism (marker of brainfunction). DA D2 Receptors

Metabolism

Repeated Drug Use Changes the Brain Weakens the Brain Dopamine System

TYROSINE

DA

DOPA

DA

DA

DA

DA

D A

DA

REPEATED USE OF COCAINE OR OTHER DRUGS REDUCES LEVELS OF DOPAMINE D2 RECEPTORS

TYROSINE

DA

DOPA

DA

DA

DA

D A D A D A

D AD AD A

DA

COCAINE

TYROSINE

DA

DOPA

DA

DA

DA

DA

D A

DA

Control Cocaine Abuser

PLEASURE

Dopamine D2 Receptors are Lower in Addiction

Cocaine

Alcohol

Heroin

Meth

control addicted Volkow et al., Neuro Learn Mem 2002.

1.5

2

2.5

3

3.5

4

4.5

15 20 25 30 35 40 45 50

DA

D2

Rec

epto

rs(R

atio

Inde

x)

20 25 30 35 40 45 501.6

1.8

2

2.2

2.4

2.6

2.8

3

3.2`

Bm

ax/K

d

Normal ControlsCocaine Abusers

D2R Overexpression in Sprague Dawleys

Over-expression of D2 receptors in rats markedly reduces alcohol intake

0102030405060

% C

hang

e D

2R

Time (days)4 6 8 10

p < 0.0005

p < 0.0005p < 0.005

p < 0.10D2R

Vec

tor

0-100

-80

-60

-40

-20

0

Time (days)4 6 8 10

p < 0.001

p < 0.001

p < 0.01

0

DA D2 Levels

D2R Overexpression In Alcohol Preferring Rats

Thanos et al., Alcohol Clin Exp Res.

Thanos, PK et al., J Neurochem, 2001.

ControlsMethamphetamine

Abusers

OFC

umol

/100

gr/m

in

4

0

Controls Alcoholics

30

40

50

60

70

80

90

2.9 3 3.1 3.2 3.3 3.4 3.5 3.6

D2 Receptors (BPND)

1 . 5 2 2 . 5 3 3 . 52 2

2 4

2 6

2 8

3 0

3 2

3 4

3 6

3 8

2 S

(

g)

30

35

40

45

50

55

60

65

1.8 2 2.2

2.4 2.6

2.8 3 3.2 3.4

Control Cocaine Abuser

DA D2 receptors

Relationship Between Brain Glucose Metabolismand Striatal D2 Receptors

Volkow et al., PNAS 2011 108(37): 15037-42

ACC

40

45

50

55

60

Controls Abusers

mic

rom

ol/1

00g/

min

ACCP < 0.01

40

45

50

55

60

Controls Abusers

mic

rom

ol/1

00g/

min

OFCP < 0.005

0.9000.9501.001.051.101.151.201.251.30

4.0 4.2 4.4 4.6 4.8 5.0

OFC

Rel

ativ

e m

etab

olis

m

0.750.800.850.900.951.001.05

4.0 4.2 4.4 4.6 4.8 5.0

CG

Rel

ativ

e m

etab

olis

m

DA D2 Receptors and Relationship to Brain Metabolismin Subjects with Family History for Alcoholism

D2R were associated with metabolism in PREFRONTAL regions the disruption of which results in impulsivity and compulsivity

D2R (Bmax/Kd)Correlations between Metabolism and D2R P <0.005

Volkow et al. Arch Gen Psychiatry 2006.

Non-Addicted Brain Addicted Brain

Dorsal StriatumMotor cortex

AmygdalaHippocampus

PFC(ACC, LPFC

BA44, lat OFC)

STOPNAcVTA

Dorsal Striatum

Motor Cortex

AmygdalaHippocampus

PFC(ACC, inferior PFC,

lateral OFC)

GONAcVTA

Volkow et al PNAS 2011.Controlled behavior Automatic behavior

Target Selection on the Basis of the Neurocircuitry of Addiction

Targets to reduce cue-induced drug seeking and to improve executive function

Targets to reduce stress-induced drug seeking and to improve mood

Compounds targeted to neurocircuitry could be beneficial not just to addiction but also to diseases for which such circuits are disrupted (i.e., ADHD, depression)

Diagram: Koob GF, Volkow ND. Neuropsychopharmacol Rev, 2010

Targets to interfere with drug reward

Antibodies reduce amount of drug in the brain

CapillaryBlood Flow

Brain

Targets drugs, not receptors

CapillaryBlood Flow

Brain

Antibodies

Vaccine

Binding sites

Immunotherapies for Opioid Use Disorder

Hwang et al., Efficacious Vaccine against Heroin Contaminated with Fentanyl. ACS Chem. Neurosci. 2018

#Rx Summit www.NationalRxDrugAbuseSummit.org

1000000

2070000

750000

410000

3150000

670000

70000250000

2910000

770000

130000

0

500000

1000000

1500000

2000000

2500000

3000000

3500000

World Drug Report, UNODC, 2015.

Number of IDU in General Population Aged 15-64,

2013 (Best)

Injection Drug Use Fuels the HIV Epidemic

Globally, there are 16 million IDU

Csete et al., Lancet 2016

In the US, close to 775,000 were past year IDUs

Lansky A et al., PLOS One 2014.

New and Innovative Opioid Addiction Treatments

• Improved opioidbased medications

• New non-opioid basedmedications

• Biologics (e.g., vaccines, antibodies)

• Non-pharmacological treatments

Opi

oid

Effe

ct Full Agonist

(Methadone)

Partial Agonist(Buprenorphine)

Antagonist(Naloxone)

Log Dose

Currently Available Medications

Rosenthal et al., Addiction 2013;105.

MAT Prevents HIV

Metzger DS et al., J AIDS 2015.

Long- vs Short-Term Buprenorphine

LT-MAT (48 weeks)ST-MAT (2 weeks)

1009080706050403020100

Baseline Week 26

p<0.05

Woody GE et al., JAIDS. 2014.

14.4%

2.5%14.1%

0

5

10

15

20

25

Buprenophine

Perc

ent

Methadone

Risky Behavior ReductionShared Needles

Injection Past 30 Days

Williams AR, Nunes E, Olfson M. Health Affairs Blog, 2017

OUD Cascade of Care in USA

Current estimatesTreatment gap90% goal

Medication Assisted Therapies Work but they are not Being Used

Addiction Specialty Programs Offering Services

As % of all programs surveyed (N=345)

Withinadopting

programs, % of eligible patients

receiving Rx

Opioid Tx Meds:

Methadone 7.8 41.3

Buprenorphine 20.9 37.3

Tablet naltrexone

22.0 10.9

Knudsen et al, 2011, J Addict Med; 5:21-27.

Substance Abuse Specialty Programs in USA

IDUs on Methadone or Buprenorphine 2009

Many Countries Reluctant to use MAT

Wolfe D et al., Lancet 2010; 376: 35-366.

Rosenthal et al., Addiction 2013;105.

We have tools: To treat patients with SUD who are HIV+ …But we have MAJOR CHALLENGES

1. Treating Substance Abusers with antiretrovirals

2. Treating HIV+ Patients for Substance Abuse

Rosenthal et al., Addiction 2013;105.

Improving Treatments for Addiction in Health Care Settings: Infectious Disease Clinics

Infectious Clinic’s-Based Buprenorphine of Opioid-Dependent HIV+ Patients vs Tx Referral

Lucas GM et al., Ann Intern Med 2010.

74%

41%

0

20

40

60

80

100Clinic-Based BUP Referred Tx

Aver

age

Part

icip

atio

n in

Opi

oid

Ago

nist

The

rapy

(%)

P<0.001

Rosenthal et al., Addiction 2013;105.

Lessons Learned from HIV Prevention:

A comprehensive approach is needed for addressing HIV including:

• Expanded and regular HIV testing

• Links to care & treatment for HIV with antiretrovirals

• Access to treatment for SUD including expanded access of MAT

• Wide availability of needle and syringe programs

John W. Ward, M.D., CDC

• MAT for IDU is a prevention strategy for HIV

• MAT improves adherence to ARV and outcomes for HIV

• MAT is still very restricted and its use should be expanded within the health care system and in criminal justice settings.

• Success in implementing MAT is necessary for achieving an AIDS free generation