1. Addiction: It’s a Brain Disease Beyond a Reasonable Doubt
Addiction is a chronic brain disease expressed as compulsive behavior within a social context. This presentation is designed to provide an overview of the neurobiology of addiction for people working in criminal justice and drug abuse treatment settings.

2. Presentation Objectives
Identify impact of substance abuse & addiction
Examine contribution of nature vs. nurture
Explain how drugs “work”
Understand how prolonged drug use changes brain circuitry
Understand how appropriate treatment can help people recover from drug abuse and addiction.

3. Addiction Medical Medical DRUGS Economic Social Neurotoxicity
AIDS
CANCER MENTAL ILLNESS
Neurotoxicity
AIDS, Cancer
Mental illness
DRUGS
The effects of drug abuse are wide ranging and affect people of all ages. Besides addiction, drug abuse is linked to a variety of health problems, including HIV/AIDS, cancer, heart disease and many more. It is costly to individuals and society, and is linked to homelessness, crime, and violence.
Social
Economic
Health care
Productivity
Accidents
Homelessness
Crime
Violence

4. Estimated Economic Cost to Society from Substance Abuse and Addiction:
Illegal drugs: $181 billion/year
Alcohol: $185 billion/year
Tobacco: $158 billion/year
Total: $524 billion/year
Surgeon General’s Report, 2004; ONDCP, 2004; Harwood, 2000.

5. Contributors to the Economic Costs of Substance Abuse and Addiction
Health care expenditures
Alcohol and drug abuse services
Medical consequences
Productivity (lost earnings)
Premature death
Impaired job performance
Institutionalized population
Incarceration
Criminal victimization
Other impacts on society
Crime
Social welfare administration
Vehicular accidents
Adapted from Harwood et al., Addiction, 1999.

6. Drug Use Correlates with Crime
Between 50% and 80% of Adult Male Arrestees Tested Positive for Illicit Drug Use in 2000
Drug Use Correlates with Crime
Drug abuse is linked to crime. The data presented are from the Arrestee Drug Abuse Monitoring (ADAM) program, funded by the National Institute of Justice (NIJ). The ADAM data, which are based on random sampling procedures, show that in 2000, high percentages (between 50 and 80 percent) of adult male arrestees in 24 metropolitan areas tested positive for illicit drugs.
2000 Arrestee Drug Abuse Monitoring: Annual Report, April 2003.

7. The Perpetrator is Involved in Drug Use in…
More than 50% of violent crimes
60-80% of child abuse and neglect cases
50-70% of theft and property crimes
75% of drug dealing
Belenko and Peugh, 1998; National Institute of Justice, 1999.

8. However… advances in science have revolutionized our fundamental views of drug abuse and addiction, showing us that: ► abuse is a preventable behavior ► addiction is a treatable disease

9. used to be
Science has come a long way in helping us understand how drugs of abuse affect the brain.

10. Your Brain on Drugs Today
1-2 Min
3-4
5-6
6-7
7-8
8-9
9-10
10-20
20-30
YELLOW shows places in brain where cocaine goes (striatum)
Front of Brain
Back of Brain
We can now measure the brain’s response to drugs of abuse in real time. This slide shows images of a human brain taken at different intervals following administration of radioactive cocaine. Because the drug was radiolabeled, scientists can see precisely where cocaine binds (yellow signal) and for how long. Such studies teach scientists more about how cocaine exerts its devastating effects.
Fowler et al., Synapse, 1989.

11. Common Myths About Drug Abuse…
Drug abuse equates to drug addiction
Alcohol is not a drug
Addiction is a moral weakness
You have to hit rock bottom to recover
You have to want treatment for it to be successful
Drug abuse is more common among minorities

12. What is Addiction? A brain disease expressed as a compulsive behavior
The continued abuse of drugs despite negative consequences
A chronic, potentially relapsing disorder
But what is addiction? We now know that while the initial decision to use drugs is voluntary, drug addiction is a disease of the brain that compels a person to continue taking drugs despite their many adverse health and life consequences.

13. Why Do People Take Drugs in The First Place?
To feel good
To have novel:
feelings
sensations
experiences
AND
to share them
To feel better
To lessen:
anxiety
worries
fears
depression
hopelessness
Research has shown that people generally take drugs to either feel good (sensation seekers, or anyone wanting to experiment with feeling high or feeling different) or to feel better (self-medicators, or individuals who take drugs in an attempt to cope with difficult problems or situations, including stress, trauma, and symptoms of mental disorders).

14. Why do some people become addicted while others do not?
Vulnerability
Why do some people become addicted while others do not?
What makes some people more vulnerable to drug addiction? Many people try drugs without getting addicted, while others do become addictedsome quickly and easily.

15. Big Genetic Contribution to Drug Abuse and Addiction…
We Know There’s a
Big Genetic Contribution to
Drug Abuse and Addiction…
….Overlapping with Environmental Influences that Help Make Addiction a Complex Disease.

16. Biology/genes Environment Biology/ Environment Interactions
It is clear today that addiction is the result of complex interactions not only among many genes but also between genes and a host of environmental factors.

17. DA Receptors and the Response to
Methylphenidate (MP)
High DA
receptor
high
Dopamine receptor level
low
Low DA receptor
The level of dopamine receptors in the brain can influence whether a person likes or dislikes the effects of a drug. Dopamine is one of many chemicals normally found in the brain and is involved in the perception of pleasure. Most abused drugs directly or indirectly increase dopamine in brain regions related to reward and motivation. Dopamine receptors are the sites on nerve cells where dopamine attaches to regulate their function.
The graph on the right side of this slide shows that individuals with a lot of dopamine receptors (top picture on the left; dopamine receptors are in yellow/red) tend to experience methylphenidate (a stimulant) as unpleasant, whereas persons with lower numbers of dopamine receptors (bottom picture on the left) find it pleasurable. This biological difference can influence the chances of re-exposure to a drug, and thus the risk of abuse or addiction.
As a group, subjects with low receptor levels found MP pleasant while those with high levels found MP unpleasant
Adapted from Volkow et al., Am. J. Psychiatry, 1999.

18. Community Peer Cluster Family Individual
Drug Abuse
Drug/Alcohol Related Traffic Accidents
Delinquency
Community Peer Cluster Family Individual
Sexually Transmitted Diseases (Including HIV/AIDS)
Academic Failure and Dropping Out of School
Suicidal Behavior
The likelihood of someone who abuses drugs then becoming addicted to them also depends on the balance of his or her level of exposure to risks and protective factors, which span the whole spectrum, from individual (genetics, developmental, behavioral) to social (family/community environment, peer pressure, economic burden, etc.) factors. The more positive these factors are, the more they will afford a measure of protection or resistance to the risks of drug abuse. Prevention programs, including behavioral skills training and environmental modification, can be designed to enhance protective factors.
Juvenile Depression
Unwanted Pregnancies
Running Away From Home

19. How Do Drugs “Work”?

20. …hoping to change their brains.
Initially, a person takes a drug
hoping to change his or her mood,
perception, or emotional state
Translation –
…hoping to change their brains.

21. We know that despite
their many differences, most abused substances enhance the dopamine and serotonin pathways

22. Two of the brain-signaling pathways targeted by drugs of abuse transmit dopamine and serotonin: Dopamine and serotonin are chemicals (also known as neurotransmitters) that are normally involved in communication between neurons in the brain. Abused substances can influence functions modulated by either or both of these chemicals. Dopamine is found in numerous brain areas (blue) related to pleasure, motivation, motor function, and saliency of stimuli or events. Serotonin, (red) plays a role in learning, memory, sleep, and mood.

23. GABA and Glutamate Role in Motivation
Basolateral Amygdala
Prefrontal Cortex
Mediodorsal Thalamus
Motor Nuclei
Ventral Pallidum
Nucleus Accumbens
Ventral Tegmental Area
At least two other neurotransmitters are also influenced by drug abuse and addiction: GABA and glutamate. Research has shown that dopamine, GABA, and glutamate are all present in interconnected brain areas that influence motivation.
Dopamine
GABA
Glutamate
Adapted from Kalivas and Nakamura, Curr. Opin. Neurobiol., 1999.

24. Circuits Involved In Drug Abuse and Addiction
All of these must be considered
in developing strategies to effectively treat addiction
Brain circuits are affected by drug abuse and addiction. The areas depicted contain the circuits that underlie feelings of reward, learning and memory, motivation and drive, and inhibitory control. Each of these brain areas and the behaviors they control must be considered when developing strategies to treat drug addiction.
PFC – prefrontal cortex; ACG – anterior cingulate gyrus; OFC – orbitofrontal cortex; SCC – subcallosal cortex; NAcc – nucleus accumbens; VP – ventral pallidum; Hipp – hippocampus; Amyg – amygdala

25. Alcohol vs. Other Drugs
We know that alcohol impairs the brain and results in addiction with repeated use in the same way as other drugs

26. Precursor Synthesis Storage Degradation Reuptake Release
= vesicle
Precursor
= neurotransmitters
Synthesis
= receptor
Storage
Degradation
Reuptake
Release
So how do abused drugs influence neurotransmission? This slide illustrates how neurons normally communicate with each other. The top part of the picture shows the end or terminal of one neuron. It contains mechanisms for synthesizing and degrading neurotransmitters that are used to communicate information between neurons. The round sack-like structures are known as vesicles and they contain neurotransmitters, such as dopamine, that are ready to be released. When a signal travels down the neuron and reaches the terminal, it causes the vesicles to spill their neurotransmitters into the synaptic cleft, or synapse. This is the space between nerve cells through which the neurotransmitter travels in order to attach to specific receptors on the second neuron (bottom of slide). Once these receptors are activated, the neurotransmitter detaches from the receptors and migrates back into the synapse where it is taken back up (reuptake) by specific transporters for reuse. Under normal conditions, this process is well-regulated.
Synaptic Cleft

27. This slide and the one that follows show how neurotransmission works specifically for dopamine. In this slide, dopamine is contained in vesicles in the first neuron. Dopamine receptors are present on the second neuron.

28. dopamine transporters
When a signal comes down the neuron, dopamine is released into the synapse. It then crosses to the second neuron where it binds to and stimulates dopamine receptors. It then crosses back to the first neuron where it is picked back up by dopamine transporters (reuptake molecules) for re-use.

29. Natural Rewards Elevate Dopamine Levels DA Concentration (% Baseline)
FOOD
SEX
200
200
NAc shell
150
150
DA Concentration (% Baseline)
100
100 15 5 10
Copulation Frequency
% of Basal DA Output
Empty 50
Box
Feeding
Natural rewards increase dopamine neurotransmission. For example, eating something that you enjoy or engaging in sexual behavior can cause dopamine levels to increase. In these graphs, dopamine is being measured inside the brains of animals, its increase shown in response to food or sex cues. This basic mechanism has been carefully shaped and calibrated by evolution to reward normal activities critical for survival. 60
120
180
Female Present
Time (min) 1 2 3 4 5 6 7 8
Sample
Number
Mounts
Intromissions
Ejaculations
Di Chiara et al., Neuroscience, 1999.
Fiorino and Phillips, J. Neuroscience, 1997.

30. But what happens when a person takes a drug
But what happens when a person takes a drug? This slide shows how cocaine is able to alter activity in the synapse. Cocaine, shown in green, attaches to dopamine transporters, preventing dopamine from being taken back up by the first neuron. This means dopamine remains in the synapse for a longer period of time where it can continue to stimulate the receptors of the second neuron. This amount of dopamine in the synapse is far greater than the increases that normally occur when a person does something enjoyable, and is what produces the euphoria initially experienced by cocaine abusers, as well as the risk for abuse.

31. Effects of Drugs on Dopamine Release
100
200
300
400
500
600
700
800
900
1000
1100 1 2 3 4
5 hr
Time After Amphetamine
% of Basal Release DA
DOPAC
HVA
Accumbens
AMPHETAMINE
100
200
300
400 1 2 3 4
5 hr
Time After Cocaine
% of Basal Release DA
DOPAC
HVA
Accumbens
COCAINE
100
150
200
250 1 2
3 hr
Time After Nicotine
% of Basal Release
Accumbens
Caudate
NICOTINE
100
150
200
250 1 2 3 4
5hr
Time After Morphine
% of Basal Release
Accumbens
0.5
1.0
2.5 10
Dose (mg/kg)
MORPHINE
Drugs of abuse increase dopamine neurotransmission. All the drugs depicted in this slide have different mechanisms of action; however, all increase activity in the reward pathway by increasing dopamine neurotransmission. Because drugs activate these brain regionsusually more effectively than natural rewardsthey have an inherent risk of being abused.
Di Chiara and Imperato, PNAS, 1988

32. prolonged drug use changes the brain in fundamental
Science has generated much
evidence showing that…
prolonged drug use changes
the brain in fundamental
and long-lasting ways

33. Dopamine D2 Receptors are Lower in Addiction
Cocaine DA DA DA DA DA DA DA DA DA DA DA DA
Meth
Reward Circuits
Non-Drug Abuser
DA D2 Receptor Availability
Alcohol
Drug-induced repeated disturbances in dopamine cell activity can lead to long-term and deleterious effects in the brain. These effects can be detected using brain imaging technologies. Positron emission tomography (PET), for example, is a powerful technique that can demonstrate functional changes in the brain. The images depicted in this slide using PET show that similar brain changes result from addiction to different substances, particularly in the structures containing dopamine. Dopamine D2 receptors are one of five receptors that bind dopamine in the brain. In this slide, the brains on the left are those of normal controls, while the brains on the right are from individuals addicted to cocaine, methamphetamine, alcohol, or heroin. The striatum (which contains the reward and motor circuitry) shows up as bright red and yellow in the normal controls, indicating numerous D2 receptors. Conversely, the brains of addicted individuals (on the right row) show a less intense signal, indicating lower levels of D2 receptors. This reduction likely stems from a chronic overstimulation of the second (post-synaptic) neuron (schematically illustrated in the right hand column), a drug-induced alteration that feeds the addict’s compulsion to abuse drugs. DA DA DA DA DA DA
Heroin
Reward Circuits
Control
Addicted
Drug Abuser

34. Dopamine Transporters in Methamphetamine Abusers
Motor Task
Loss of dopamine
transporters in the meth
abusers may result in
slowing of motor
reactions. 7 8 9 10 11 12 13
1.0
1.2
1.4
1.6
1.8
2.0
Time Gait
(seconds) 4 6 14 16
Delayed Recall
(words remembered)
Dopamine Transporter
Bmax/Kd
Normal Control
Memory task
Loss of dopamine transporters
in the meth abusers may result
in memory impairment.
Dopamine transporters decrease and mental function is compromised when a person abuses methamphetamine. The brain image at the top is from a normal control. The striatum is brightly lit in red and yellow, indicating the presence of many dopamine transporters. In contrast, the brain of a methamphetamine abuser (bottom) shows much less binding in the striatum, indicating that methamphetamine abusers suffer significant reductions in dopamine transporters. But what does this mean functionally? The graphs on the right side show the impact on motor and memory tasks of this methamphetamine-driven decrease in dopamine transporters. The magnitude of the decline in number of dopamine transporters corresponds to the extent of motor and memory impairment.
Methamphetamine Abuser
Volkow et al., Am. J. Psychiatry,

35. Brain changes resulting from prolonged use of drugs may compromise
Implication:
Brain changes resulting from
prolonged use of drugs
may compromise
mental and motor functions

36. Conditioned Association
CRAVING INDUCTION IN A PET SETTING
N = 13
DCRAVING 5 4 3 2 1 -1
Neutral
Cocaine
STIMULI
Nature Video Cocaine Video
Conditioned
Association
1.5 .5
1.0
2.0
2.5
Former addicts report overwhelming urges or craving for drugs in response to cues previously associated with drug taking, which often leads to relapse. This phenomenon can be examined experimentally through PET monitoring of brain responses to video depictions of drug-related and non-drug-related images. The bar graph on the left illustrates strong craving induced by cocaine-associated stimuli in a person addicted to cocaine. The cocaine video increased brain activity (bottom right images) in two areas: the amygdala (not shown) and the anterior cingulate gyrus. The amygdala is involved in emotional response and learning while the anterior cingulate is involved in evaluating the wisdom of and inhibiting impulsive behaviors.
Childress et al., Am. J. Psychiatry, 1999

37. Memories Appear to Be A Critical Part of Addiction
“Its about people, places and things…”

38. Cocaine Craving:
Population (Cocaine Users, Controls) x Film (cocaine, erotic)
Cingulate
Ant. Cing.
Signal Intensity (AU)
Natural rewards become devalued in drug abusers, as drug-associated cues usurp the motivational circuits. Cocaine videos activate the brain of a drug abuser more than erotic stimuli. The bar graphs on the left show that specific brain areas in control individuals become strongly activated by erotic but not by cocaine-related films (yellow bar), while the exact opposite pattern is seen in cocaine abusers (blue bar). These results suggest that addicted individuals have an impaired capacity to extract pleasure out of normally enjoyable activities or stimuli.
Cocaine Film
IFG
Controls Cocaine Users
Garavan et al., Am. J. Psychiatry, 2000.

39. Drugs Are Usurping
Brain Circuits
and
Motivational
Priorities

40. Treatment and the Cycle of Addiction

41. Addiction is the Quintessential Biobehavioral Disorder

42. Drug Addiction: A Complex Behavioral and Neurobiological Disorder
Historical
Drugs
Physiological
- Prior experience - Expectation - Learning
- Genetics - Circadian rhythms - Disease states - Gender
Environmental
- Social interactions - Stress - Conditioned stimuli
Brain Mechanisms
Behavior
Environment

43. Addiction Changes Brain Circuits
Drive
Saliency
Memory
Control
Non-Addicted Brain
NOT GO
Addicted Brain
Addiction changes brain circuitry making it hard to “apply the brakes” to detrimental behaviors. In the non-addicted brain, control mechanisms constantly assess the value of stimuli and the appropriateness of the planned response, applying inhibitory control as needed. In the addicted brain, this control circuit becomes impaired through drug abuse, losing much of its inhibitory power over the circuits that drive response to stimuli deemed salient.
Source: Adapted from Volkow et al., Neuropharmacology, 2004.

44. This is why addicts can’t just quit
This is why treatment is essential

45. Treating a Biobehavioral Disorder Must Go Beyond Just Fixing the Chemistry
Pharmacological (medications)
Behavioral Therapies
Medical and Social Services

46. We Need to Treat the
Whole Person!
In Social Context

47. Treatment Can Work
Treatment Can Work. More than 30 years of research have shown this to be true. Behavioral therapies can engage people in treatment, modify their attitudes and behaviors related to drug abuse, and increase their life skills. Medications are now available to treat opioid, alcohol, and tobacco addiction, while others are on the horizon. And, behavioral therapies enhance the effectiveness of medications and can help people stay in treatment longer.

48. But, drug addiction is a chronic illness with relapse rates similar to those of hypertension, diabetes, and asthma
McLellan et al., JAMA, 2000.

49. Relapse Rates Are Similar for Drug Addiction & Other Chronic Illnesses
Type I
Diabetes 10 20 30 40 50 60 70 80 90
100
Hypertension
Asthma
40 to 60%
30 to 50%
50 to 70%
Percent of Patients Who Relapse
Relapse rates are similar for drug addiction and other well-characterized chronic illnesses. This slide compares relapse rates for drug-addicted patients and those suffering from diabetes, hypertension, and asthma. Relapse is common and similar across these illnesses (as is adherence to medication). Thus, drug addiction should be treated and evaluated like any other chronic illness.
McLellan et al., JAMA, 2000.

50. Addiction is Similar to Other Chronic Illnesses Because:
Recovery from it--protracted abstinence and restored functioning--is often a long-term process requiring repeated treatments
Relapses to drug abuse can occur during or after successful treatment episodes
Participation in self-help support programs during and following treatment can be helpful in sustaining long-term recovery
Therefore…

51. There is a right way and a wrong way to
Measure the Outcome of Treating
Chronic Illnesses like Addiction
Hypertension Tx
Stage of Tx
YES
Addiction Tx NO
Drug addiction treatments are not evaluated the same away as treatments for other chronic, relapsing diseases. This leads to the misperception that treatment doesn’t work for addiction. For other chronic diseases like diabetes or hypertension (left), we consider treatment effective if it works while a patient is adhering to it. And we recognize that the effects may not last very long if treatment stops or patients are not in contact with their health care provider. We often expect relapse and do not devalue the treatment’s success if it occurs. Conversely, drug addiction (right), has historically been treated as an acute illness, with intervention success routinely (and wrongly) evaluated by comparing the disease state before treatment and after discharge, sometimes months or years later. Thus, treatment is considered a failure if its effects are not sustained. This approach fuels the misperception that drug abuse treatment does not work. On the contrary, treatment should to be reinstated as needed, just as it is for other chronic, relapsing conditions.

52. Full recovery is a challenge but it is possible …

53. DAT Recovery with prolonged abstinence from methamphetamine
[C-11]d-threo-methylphenidate
DAT Recovery
with prolonged
abstinence from
methamphetamine
Normal Control
high
Methamphetamine Abuser
(1 month detoxification)
low
Recovery of the brain from addiction takes time, but it does happen. This slide shows images of dopamine transporter (DAT) levels in three brains: (1) a healthy control (top); (2) a methamphetamine abuser one month after discontinuing drug abuse (middle); and (3) a methamphetamine abuser after 24 months of abstinence (bottom). The control brain shows a robust concentration of dopamine transporters in the striatum (red and yellow), while the methamphetamine abuser has a dramatic drop in DATs, even a month after drug abuse has stopped. Two years of abstinence however, allows a near full return of DATs to normal levels. Still, some of the behavioral effects of methamphetamine do not completely return to normal (not shown). This means that it can take a long time to recover from methamphetamine abuse, but recovery is possible.
Methamphetamine Abuser
(14 month abstinent)
Volkow et al., J. Neuroscience, 2001.

54. Treatment Reduces Drug Use and Recidivism
No treatment
CREST Dropouts
CREST Completers
+ Aftercare
Delaware Work Release Therapeutic Community (CREST) + Aftercare
3 Years After Release (N=448)
p < 0.05,
compared to No Treatment group
Percentage of Participants
Drug-Free
Arrest-Free
Drug abuse treatment works and brings about reductions not just in drug abuse, but also in criminal recidivism. These reductions in turn yield significant cost savings and provide hope for families and communities devastated by addiction.

55. We Need to Keep Our Eye on
In Treating Addiction…
We Need to Keep Our Eye on
the Real Target
Abstinence
Functionality in
Family, Work
and Community

56. Since it was established in 1974, NIDA has supported research on drug
abuse treatment for individuals who are
involved with the criminal justice system.
Treating Criminal Justice-Involved Drug Abusers and Addicts. Drug abusers may come into contact with the criminal justice system earlier than with other health or social systems. Thus, the period of involvement with the criminal justice system may offer an opportunity to engage individuals in a treatment that can shorten a career of drug abuse and related crime. Research supports the efficacy of combining criminal justice sanctions and drug abuse treatment. The broad implementation of prison- as well as community-based treatment programs for criminal justice populations is one of NIDA’s top priorities.

57. Volkow et al., J. Neuroscience, 2001.
Surgeon General’s Report, 2004; ONDCP, 2004; Harwood, 2000.
Adapted from Harwood et al., Addiction, 1999.
2000 Arrestee Drug Abuse Monitoring: Annual Report, April 2003.
Belenko and Peugh, 1998; National Institute of Justice, 1999.
Fowler et al., Synapse, 1989.
Adapted from Volkow et al., Am. J. Psychiatry, 1999.
Adapted from Kalivas and Nakamura, Curr. Opin. Neurobiol., 1999.
Di Chiara et al., Neuroscience, 1999.
Fiorino and Phillips, J. Neuroscience, 1997.
Di Chiara and Imperato, PNAS, 1988
Volkow et al., Am. J. Psychiatry, 2001
Garavan et al., Am. J. Psychiatry, 2000.
Childress et al., Am. J. Psychiatry, 1999.
Source: Adapted from Volkow et al., Neuropharmacology, 2004.
McLellan et al., JAMA, 2000.
Volkow et al., J. Neuroscience, 2001.

58. We want to thank TASC, Inc
We want to thank TASC, Inc., of Illinois for their contribution to this presentation.