The Science of Addiction: Implications for Policy Wilson M The Science of Addiction: Implications for Policy Wilson M. Compton, MD, MPE Director, Division of Epidemiology, Services, and Prevention Research National Institute on Drug Abuse USA

Addictions are common, developmental brain diseases expressed as compulsive behavior through continued use of a drug despite negative consequences: Onset depends on many intrinsic and extrinsic factors. Biology Genes/Development Environment DRUG/ALCOHOL Brain Mechanisms Addiction

Addictions are brain diseases Human development is key Treatment can be based on neuroscience advances Policies need to account for the nature of addictive disorders

Addictions are brain diseases Human development is key Treatment can be based on neuroscience advances Policies need to account for the nature of addictive disorders

ADDICTION IS A DISEASE OF THE BRAIN as other diseases it affects the tissue function Control Cocaine Abuser Decreased Brain Metabolism in Drug Abuse High Low Decreased Heart Metabolism in Heart Disease Healthy Heart Diseased Heart Sources: From the laboratories of Drs. N. Volkow and H. Schelbert

Addictions are brain diseases Human development is key Treatment can be based on neuroscience advances Policies need to account for the nature of addictive disorders

Addiction Is Developmental Age of Onset of Drug Abuse and Dependence Addiction is also characterized as a developmental disorder characterized by increased risk for substance use disorder for tobacco MJ and alcohol There are many factor that contribute to the increase in incidence including -Social/ environmental factors - Genetic and Neurobiological factors (Sowell brain volume subtraction method between normal 12-16 year old adolescents and 23-30 year old young adults revealed parietal, temporal and occipital lobes showed little maturational change but, importantly, dorsal, medial and lateral regions of the frontal lobes (purple) those regions involved in executive function and inhibitory control were less developed. Adolescents with risk haplotype on Chromosome 15 that start smoking before age 15 go on to become more dependent to tobacco as adults than those with other haplotypes Universal Prevention intervention research is aimed at developing and testing programs that can reduce drug initiation and use during this vulnerable developmental period. Age of Onset of Drug Abuse and Dependence Source: Compton, et al. Archives of General Psychiatry 2007. NESARC Study.

Reinforcers (per session) Effects of a Social Stressor on Brain Dopamine D2 Receptors and Propensity to Administer Drugs * S .003 .01 .03 .1 10 20 30 40 50 Reinforcers (per session) Cocaine (mg/kg/injection) Dominant Subordinate Individually Housed Becomes Subordinate Stress remains Group Housed Becomes Dominant No longer stressed Social Setting Can Change Neurobiology Morgan, D. et al. Nature Neuroscience, 2002.

Adverse Childhood Experiences (ACE) and Illicit Drug Use (n = 8603) 2 4 6 8 10 1 3 5 Odds ratio ACE Score Ever Addicted 1.0 SR Dube, et al. PEDIATRICS 111: 564-572, 2003 9

Social Neglect During Early Childhood Decreases Brain Connectivity r = -0.604, p=.01 Children with deprivation (n=17) vs controls (n=15) had decreased connectivity in uncinate fasciculus (connects amygdala with frontal cortex), proportional to time in orphanage. This could facilitate heightened emotional reactivity and impaired cognitive control. Govindan et al., Cereb Cortex 2009

A gradient of childhood self-control predicts health, wealth, and public safety (Dunedin Study; 1000+ children) Health Wealth Criminal behavior Children with low self-control had poorer health, more wealth problems, more single-parent child rearing, and more criminal convictions and drug use than those with high self-control Moffitt et al., PNAS 2011 Since self-control can be improved by interventions early childhood intervention that enhances self-control is likely to bring a greater return on investment than harm reduction programs targeting adolescents alone.

Nurse Home Visiting during pregnancy and the first two years of life Results from the 2008 National Survey on Drug Use and Health (NSDUH) Substance Abuse and Mental Health Services Administration Nurse Home Visiting during pregnancy and the first two years of life has an impact on substance use, mental health and academic achievement at 12 years of age Percent of Children Who Used Tobacco, Alcohol, or Marijuana (Last 30 Days) Child Age 12 Percent of Children with Internalizing Problems (Borderline or Clinical) Child Age 12 PIAT Scores - Reading & Math – Age 12 (Born to Low-Resource Mothers) Percent of Mothers with Role Impairment due to Alcohol or Drug Use – Child Age 12 Arch Pediatr Adoles Med, 164(5) 412-418, 2010

Addictions are brain diseases Human development is key Treatment can be based on neuroscience advances Policies need to account for the nature of addictive disorders

Dopamine Movement Motivation Addiction Reward & well-being It’s About Dopamine (mostly) Dopamine is the brain’s primary “pleasure chemical” Dopamine plays a role in attention, problem solving, and the anticipation of reward Dopamine is implicated in the drug high, as well as in the craving that accompanies withdrawal. Dopamine is a brain chemical involved in many different functions including movement, motivation, reward — and addiction. Nearly all drugs of abuse directly or indirectly increase dopamine in the pleasure and motivation pathways and in so doing, alter the normal communication between neurons. Addiction Reward & well-being

But Dopamine is only Part of the Story Other neurotransmitter systems are also implicated Serotonin Regulates mood, sleep, etc. Glutamate Regulates learning and memory, etc. And Others Dopamine is an important brain chemical in drug abuse and addiction, but other brain systems and brain chemicals are also involved. Serotonin and glutamate neurotransmitter systems, for example, are among those affected. These neurotransmitters are important regulators of mood, sleep, learning and memory, and more. These and other brain neurochemicals and electrical signals are responsible for your ability to think, move, feel, and behave.

Why Can’t Addicts Just Quit? Key Question: Why Can’t Addicts Just Quit?

Drug Abuse and Addiction Circuits Involved In Drug Abuse and Addiction PFC ACG EXECUTIVE FUNCTION/ INHIBITORY CONTROL OFC SCC MOTIVATION/ DRIVE Hipp Amyg MEMORY/ LEARNING NAcc VP REWARD

Drugs of Abuse Engage Systems in the Motivation Pathways of the Brain NAcc VP REWARD Reward Circuit Drugs of Abuse Engage Systems in the Motivation Pathways of the Brain

Natural Rewards Elevate DA Concentration (% Baseline) Dopamine Levels Food Sex 200 200 NAc shell 150 150 Natural rewards stimulate dopamine neurotransmission. Eating something that you enjoy or being stimulated sexually can cause dopamine levels to increase. In these graphs, dopamine is being measured inside the brains of animals. Its increase is shown in response to food or sex cues. This basic mechanism of controlled dopamine release and reuptake has been carefully shaped and calibrated by evolution to reward normal activities critical for our survival. DA Concentration (% Baseline) % of Basal DA Output 100 100 Empty 50 Box Feeding Female Present 1 2 3 4 5 6 7 8 60 120 180 Sample Number Time (min) Di Chiara et al., Neuroscience, 1999.,Fiorino and Phillips, J. Neuroscience, 1997. 19

All Drugs Abused by Humans Raise Brain Dopamine Levels in the Nucleus Accumbens ` Time After Methamphetamine Dopamine (nM) METHAMPHETAMINE 2000 1500 1000 500 5 1 2.5 Dose (mg/kg IV) 0 20 40 60 80min 250 NICOTINE 200 % of Basal Release 150 100 1 2 3 hr Time After Nicotine Nestler, Nature Neurosci, 2005 Di Chiara et al.

Increases in Dopamine are Associated with Perceived “High” NAcc VP REWARD T Y R O S I N E T Y R O S I N E D O P A D O P A D A D A DA D A DA D A D A -10 10 20 30 40 -2 2 4 6 8 Self-Reports (0-10) Change in Dopamine Bmax/kd (Placebo - MP) “High” D A D A raclopride D A D A D A m e t h y l p n i d a D A D A raclopride D A R R D A D A D A R R R R Volkow et al., JPET 291(1):409-415, 1999. 21

“People, Places and Things…” Hipp Amyg MEMORY/ LEARNING 2. Memory circuit “People, Places and Things…”

Cocaine Craving: Population (Cocaine Users, Controls) x Film (cocaine ) Cingulate Ant Cing Signal Intensity (AU) Cocaine Film IFG Controls Cocaine Users Garavan et al A .J. Psych 2000

Cocaine Craving: Population (Cocaine Users, Controls) x Film (cocaine, erotic) Cingulate Ant Cing Signal Intensity (AU) IFG Controls Cocaine Users Garavan et al A .J. Psych 2000

Volkow et al J Neuroscience 2006 Dopamine Release Increases when Viewing Cocaine Cues: [11C]Raclopride Binding In Cocaine Abusers (n=18) Viewing a Neutral and a Cocaine-Cue Video Neutral video Viewing a video of cocaine scenes decreased specific binding of [11C]raclopride presumably from DA increases Volkow et al J Neuroscience 2006

ACG OFC SCC INHIBITORY CONTROL EXECUTIVE FUNCTION PFC MOTIVATION/ DRIVE Motivation & Executive Control Circuits Dopamine is also associated with motivation and executive function via regulation of frontal activity.

Relationship Between Brain Glucose Metabolism and Striatal D2 Receptors 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) 35 45 55 65 1.8 2 2.2 2.4 2.6 2.8 Control Cocaine Abuser control addicted Brain glucose metabolism Controls Methamphetamine Abusers umol/100gr/min OFC 4 Controls Alcoholics Volkow et al., PNAS 2011 108(37): 15037-42 DA D2 receptors

ADDICTION Becomes severely disrupted in The fine balance in connections that normally exists between brain areas active in reward, motivation, learning and memory, and inhibitory control EXECUTIVE FUNCTION PFC ACG INHIBITORY CONTROL Hipp OFC REWARD SCC NAcc VP MOTIVATION/ DRIVE Amyg MEMORY/ LEARNING Becomes severely disrupted in ADDICTION

GO Non-Addicted Brain Addicted Brain STOP Memory Memory Stress Drive Memory Saliency Control Drive OFC Saliency NAc Memory Amygdala Control CG Drive Memory Saliency STOP GO Stress Reactivity Stress Reactivity

Effective Strategies Attend to Multiple Aspects of Addiction: Behavior Biology Social Context

Improving Prefrontal Function A Double Blind, Placebo Controlled Trial Of NEPICASTAT (Dβh Inhibitor) In Cocaine Dependence[Biotie/NIDA] Nepicastat attenuates cue-induced reinstatement of cocaine seeking Nepicastat increases DA in PFC (but not in Nac) Schroeder et al., Neuropsychopharmacology. 2013 Devoto et al., Addict Biol. 2013

Treatment Clinical Trials Network (CTN) National Drug Abuse Treatment Clinical Trials Network (CTN) NIDA Criminal Justice Drug Abuse Treatment Studies (CJ-DATS) The CTN framework consists of thirteen Nodes linked with Community-based Treatment programs The sites for these networks span the us and provide an extensive net opportunity to test the efficacy of novel treatment for addiction in both a public health and public safety environment 50-66% of inmates meeting standard diagnostic criteria for alcohol/drug dependence or abuse, according to the Bureau of Justice Statistics. Mumola CJ and Kerberg JC. Drug use and dependence, state and federal prisoners, 1004. Washington, DC: U.S. Department of Justice, Office of Justice Programs, Bureau of Justice Statistics, 2006. The vast majority of criminal offenders who would benefit from treatment (80-85%) do not receive it, Mumola CJ and Kerberg JC. Drug use and dependence, state and federal prisoners, 1004. Washington, DC: U.S. Department of Justice, Office of Justice Programs, Bureau of Justice Statistics, 2006. Karberg JC and James DJ. Substance dependence, abuse, and treatment of jail inmates, 2002. Washington, DC.: Office of Justice Programs, Bureau of Justice Statistics, 2005. CTN Sites Research Centers

Addictions are brain diseases Human development is key Treatment can be based on neuroscience advances Policies need to account for the nature of addictive disorders

Brain and Behavioral Impact of Televised Anti-Tobacco Public Service Announcements: Predictive Value Left, dMPFC activation associated with AS by MSV interaction. Statistical map (yellow-red scale) is displayed over the MNI brain template and thresholded at z = 3.1 (cluster corrected at p < 0.001). Right, Correlation between percentage BOLD signal change in dMPFC and predicted cotinine levels at 1 month follow-up, adjusting for the baseline cotinine levels and AS groups. Left, dMPFC activation associated with argument strength (AS) by “message sensation value” MSV interaction predicted cotinine levels one month after add presentation. Wang A et al. J. Neurosci. 2013;33:7420-7427

Addressing Drugs and Crime Public Health Approach - disease - treatment Public Safety Approach - illegal behavior - punish High Attrition High Recidivism

Successful Reentry Programs Use an Integrated Public Health-Public Safety Strategy Close supervision Community-based treatment Blends functions of criminal justice and treatment systems to optimize outcomes Consequences for noncompliance are certain and immediate Opportunity to avoid incarceration or criminal record

Summary: Drug Addiction is a Brain Disease Involving Reward, Memory and Control Circuits Addiction comes about by laying down and strengthening new memory connections in various circuits in the brain. Long-lasting brain changes are responsible for the distortions of thought and emotionthat characterize addicts, including the compulsion to use drugs that is the essence of addiction. Policies to prevent and treat addiction can benefit from an understanding of the science of addiction.

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