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