NEUROPHARMACOLOGY AND ADDICTION CHRISTOPHER M. JONES, PHARMD, MPH

NEUROPHARMACOLOGY AND ADDICTION CHRISTOPHER M. JONES, PHARMD, MPH

Disclosures This presentation does not represent the views of the US Public Health Service or the US Food and Drug Administration The majority of this presentation is drawn from presentations from colleagues at NIDA and from presentations I have given as an employee of the Centers for Disease Control and Prevention

Advances in science have revolutionized our fundamental views of drug abuse and addiction.

Your Brain on Drugs Today YELLOW shows places in brain where cocaine binds (e.g., striatum) Fowler et al., Synapse, 1989.

Addiction is Like Other Diseases Ø Ø Ø Ø It is preventable It is treatable It changes biology If untreated, it can last a lifetime Decreased Brain Metabolism in Drug Abuser High Decreased Heart Metabolism in Heart Disease Patient Healthy Brain Diseased Brain/ Cocaine Abuser Low Healthy Heart Diseased Heart

Addiction Involves Multiple Factors

Addiction Is A Developmental Disease that starts in adolescence and childhood % in each age group who develop first-time dependence 1.8%" 1.6%" 1.4%" 1.2%" 1.0%" 0.8%" 0.6%" 0.4%" 0.2%" TOBACCO 0.0%" 5" 10" 15" 21" 25" 30" 35" 40" 45" 50" 55" 60" 65" 5" CANNABIS ALCOHOL Age Age at tobacco, alcohol, and cannabis dependence per DSM IV National Epidemiologic Survey on Alcohol and Related Conditions, 2003.

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

Drugs can be Imposters of Brain Messages

Drugs of abuse and their targets in the brain Substance Alcohol Opioids Stimulants Benzodiazepines Marijuana Primary Target(s) in the Brain GABA-A; NMDA Opioid Receptors Dopamine Transporter GABA-A CB1 receptors

Movement Motivation Dopamine Addiction Reward & well-being

Donald Bliss, MAPB, Medical Illustration The Neuron: How the Brain s Messaging System Works Dendrites Cell body (the cell s life support center) Neuronal Impulse Axon Terminal branches of axon Myelin sheath

dopamine transporters

Natural Rewards Elevate Dopamine Levels % of Basal DA Output 200 150 100 50 0 Food NAc shell Empty Box Feeding 0 60 120 180 Time (min) DA Concentration (% Baseline) 200 150 100 Sample Number Sex Female Present 1 2 3 4 5 6 7 8 Di Chiara et al., Neuroscience, 1999.,Fiorino and Phillips, J. Neuroscience, 1997.

Effects of Drugs on Dopamine Release % of Basal Release 1100 1000 900 800 700 600 500 400 300 200 100 0 % of Basal Release 250 200 150 100 Amphetamine Accumbens DA DOPAC HVA 0 1 2 3 4 5 hr Nicotine 0 0 1 2 3 hr Time After Drug Di Chiara and Imperato, PNAS, 1988 Accumbens Caudate % of Basal Release % of Basal Release 400 300 200 100 0 250 200 150 100 0 Accumbens Cocaine DA DOPAC HVA 0 1 2 3 4 5 hr Accumbens Morphine Dose 0.5 mg/kg! 1.0 mg/kg! 2.5 mg/kg! 10 mg/kg! 0 1 2 3 4 5 hr Time After Drug

But Dopamine is only Part of the Story Scientific research has shown that other neurotransmitter systems are also affected: Serotonin Regulates mood, sleep, etc. Glutamate Regulates learning and memory, etc.

Science Has Generated Much Evidence Showing That Prolonged Drug Use Changes the Brain In Fundamental and Long-Lasting Ways

AND We Have Evidence That These Changes Can Be Both Structural and Functional

Structurally Neuronal Dendrites in the Nucleus Accumbens Saline Amph Robinson & Kolb, Journal of Neuroscience, Volume: 1997

Functionally Dopamine D2 Receptors are Decreased by Addiction Cocaine DA D2 Receptor Availability Meth Alcohol Heroin Control Addicted

Dopamine Transporters in Methamphetamine Abusers Normal Control Methamphetamine Abuser Dopamine Transporter Bmax/Kd 2.0 1.8 1.6 1.4 1.2 1.0 7 8 9 10 11 12 13 Time Gait (seconds) 2.0 1.8 1.6 1.4 1.2 1.0 16 14 12 10 8 6 Delayed Recall (words remembered) Volkow et al., Am. J. Psychiatry, 2001. 4 Motor Task Loss of dopamine transporters in methamphetamine abusers may result in slowing of motor reactions. Memory Task Loss of dopamine transporters in methamphetamine abusers may result in memory impairment.

Implication? Brain changes resulting from prolonged use of drugs may compromise mental AND motor function.

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

Vulnerability Why do some people become addicted to drugs while others do not?

Individual Differences in Response to Drugs: DA Receptors influence drug liking High DA receptor high Low DA receptor low 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.

Genetics is a Big Contributor to the Risk of Addiction And The Nature of this Contribution Is Extremely Complex

What Other Biological Factors Contribute to Addiction--Comorbidity 40 Prevalence of Drug Disorders Prevalence of Nicotine Addiction Percent 35 30 25 20 15 Percent 80 60 40 10 5 0 20 0

What Environmental Factors Contribute to Addiction? Stress Early physical or sexual abuse Witnessing violence Peers who use drugs Drug availability

Social Stressor Affects Brain DA D2 Receptors and Drug Self-Administration Individually Housed Becomes Dominant No longer stressed Group Housed 50 40 Subordinate Dominant Reinforcers (per session) 30 20 * * Becomes Subordinate Stress remains 10 0 S.003.01.03.1 Cocaine (mg/kg/injection) Morgan, D. et al., Nature Neuroscience, 2002.

Why Can t People with Addiction Just Quit? Non-Addicted Brain Control Addicted Brain Control Saliency Drive NO GO Saliency Drive GO Memory Memory Because Addiction Changes Brain Circuits Adapted from Volkow et al., Neuropharmacology, 2004.

Treating a Biobehavioral Disorder Must Go Beyond Just Fixing the Chemistry We Need to Treat the Whole Person! Pharmacological Treatments (Medications) Behavioral Therapies Medical Services Social Services In Social Context

Addiction is Similar to Other Chronic Illnesses Because: It has biological and behavioral components, both of which must be addressed during treatment. Recovery from it--protracted abstinence and restored functioning--is often a long-term process requiring repeated episodes of treatment. Relapses can occur during or after treatment, and signal a need for treatment adjustment or reinstatement. Participation in support programs during and following treatment can be helpful in sustaining long-term recovery Therefore

Full recovery is a challenge but it is possible

[C-11]d-threo-methylphenidate DAT Recovery with prolonged abstinence from methamphetamine Normal Control Methamphetamine Abuser (1 month abstinent) high low Volkow et al., J. Neuroscience, 2001. Methamphetamine Abuser (14 months abstinent)

So why is understanding addiction so important

Past month illicit drug use by age group, US, 2012! SAMHSA NSDUH 2013"

Past year initiates of specific illicit drugs among person 12 years and older, US, 2012 (number in thousands)! SAMHSA NSDUH 2013"

Emergency department visits related to drug misuse or abuse, US, 2004-2011! SAMHSA DAWN 2004-2011"

Most common drugs associated with misuse or abuse ED visits, US, 2011! SAMHSA DAWN 2011"

Rate of ED visits related to specific drugs of abuse by age group, US, 2011! SAMHSA DAWN 2011 "

Primary Substance of Abuse at Treatment Admission, US, 2000-2010! Alcohol only! Heroin! Cocaine! Stimulants! Alcohol w/secondary drug! Other opiates! Marijuana/hashish! Other drugs! 18! Admissions per 10,000 Population! 16! 14! 12! 10! 8! 6! 4! 2! 0! 2000! 2001! 2002! 2003! 2004! 2005! 2006! 2007! 2008! 2009! 2010! Year! SAMHSA Treatment Episode Data Set, 2000-2010.

Drug overdose death rates continue to increase; unprecedented death rate! Motor Vehicle Traffic" Drug Poisoning (Overdose)" 25" Deaths per 100,000 population! 20" 15" 10" 5" 0" 1980" 1982" 1984" 1986" 1988" 1990" 1992" 1994" 1996" 1998" 2000" 2002" 2004" 2006" 2008" 2010" Year! NCHS Data Brief, December, 2011, Updated with 2009 and 2010 mortality data"

Drug overdose deaths outnumbered motor vehicle traffic deaths in 10 states in 2005! More deaths from drug overdose CDC NVSS, MCOD. 2010 "

By 2010, drug overdose deaths outnumbered motor vehicle traffic deaths in 31 states! CDC NVSS, MCOD. 2010 " More deaths from drug overdose

Drug overdose death rates by age:! US, 1999-2010! 45-54 35-44 25-34 55-64 15-24 65 and over CDC/NCHS, National Vital Statistics System

Drug overdose deaths by major drug type, US, 1999-2010! 18,000! Opioids! Heroin! Cocaine! Benzodiazepines! 16,000! 14,000! Number of Deaths! 12,000! 10,000! 8,000! 6,000! 4,000! 2,000! 0! 1999! 2000! 2001! 2002! 2003! 2004! 2005! 2006! 2007! 2008! 2009! 2010! Year! CDC/NCHS National Vital Statistics System, CDC Wonder. Updated with 2010 mortality. "

Opioid analgesics and other prescription drugs commonly involved in overdose deaths! 18,000 16,000 14,000 12,000 Ddeaths 10,000 8,000 6,000 4,000 2,000 0 Drug Class Jones CM et al Pharmaceutical overdose deaths, United States, 2010. JAMA 2013 and CDC/NCHS NVSS MCOD 2010"

Increase in heroin use has occurred among people who were past year nonmedical users of opioid analgesics! Largest % of heroin users in 2008-2010! Jones, C.M., Heroin use and heroin use risk behaviors among nonmedical users of prescription opioid pain relievers United States, 2002 2004 and 2008 2010. Drug Alcohol Depend. (2013), http://dx.doi.org/10.1016/j.drugalcdep.2013.01.007 "

Majority of people who use both heroin and opioid analgesics report using opioid analgesics before initiating heroin! 100 90 80 Percent 70 60 50 40 30 20 10 0 69.1 12.4 18.4 1-29 Days PYNMU 76.4 16.9 82.6 11.2 77.4 12.9 6.7 6.2 9.7 30-99 Days PYNMU 100-365 Days PYNMU Any PYNMU Age first use opioid analgesics before heroin Age first use opioid analgesics same as heroin Age first use heroin before opioid analgesics Frequency of Past Year Nonmedical Use of Opioid Analgesics, 2008-2010 Jones, C.M., Heroin use and heroin use risk behaviors among nonmedical users of prescription opioid pain relievers United States, 2002 2004 and 2008 2010. Drug Alcohol Depend. (2013), http://dx.doi.org/10.1016/j.drugalcdep.2013.01.007 "

Frequent nonmedical users of opioid analgesics more likely to engage in risky substance use behaviors! Characteristic 1-29 Days of PYNMU of Opioid Pain Relievers 30-99 Days of PYNMU of Opioid Pain Relievers 100-365 Days of PYNMU of Opioid Pain Relievers aor (95% CI) aor (95% CI) aor (95% CI) Past Year Heroin Use referent 2.8 (1.7-4.5) 6.4 (3.7-11.1) Ever Inject Heroin referent 1.6 (0.9-2.9) 4.3 (2.5-7.3) Ever Inject Opioid Pain Relievers Past Year Heroin Abuse or Dependence Past Year Opioid Pain Reliever Abuse or Dependence Heroin Fairly or Very Easy to Obtain referent 3.8 (1.9-7.8) 13.3 (7.7-23.0) referent 3.2 (1.7-6.1) 7.8 (4.7-12.8) referent 2.9 (2.3-3.8) 8.9 (7.1-11.3) referent 1.4 (1.1-1.7) 2.1 (1.8-2.6) Abbreviations: PYNMU, past year nonmedical use; aor, adjusted Odds Ratio; 95% CI, 95% Confidence Interval 1 Odds ratio adjusted for sex, age, race/ethnicity, total family income, and county type Jones, C.M., Heroin use and heroin use risk behaviors among nonmedical users of prescription opioid pain relievers United States, 2002 2004 and 2008 2010. Drug Alcohol Depend. (2013), http://dx.doi.org/10.1016/j.drugalcdep.2013.01.007 "

Conclusions! q Addiction is a disease of the brain! q Understanding the neuropharmacology and toxicology of addiction is critical to developing effective treatments! q Recovery is possible! q The public health consequences of addiction are significant!

Thank You Questions?