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Neurobiology of Addiction. Mark Publicker, MD FASAM Medical Director Mercy Recovery Center. Addiction. A chronic but treatable brain disease characterized by loss of control compulsive use use despite known harm relapse. Comorbid substance abuse. Common problem in psychiatric patients

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neurobiology of addiction

Neurobiology of Addiction

Mark Publicker, MD FASAM

Medical Director

Mercy Recovery Center

addiction
Addiction
  • A chronic but treatable brain disease characterized by
    • loss of control
    • compulsive use
    • use despite known harm
    • relapse
comorbid substance abuse
Comorbid substance abuse
  • Common problem in psychiatric patients
  • Contributes to treatment refractoriness, non-compliance and increased health services utilization and cost
rand survey of care 2001
Rand Survey of Care, 2001
  • 3% US population has co-occuring disorders
  • Of these:
    • 72% received no treatment in previous 12 months
    • Only 8% received both mental and substance abuse treatment
    • Only 23% of those in treatment received “appropriate treatment”
co morbid psychiatric disorders
Depression

Anxiety disorders

Bipolar disorder

Schizophrenia

ADHD

PTSD

ASP

Axis II disorders

Co-morbid psychiatric disorders
epidemiology
Epidemiology
  • 50% lifetime prevalence of substance abuse disorders for psychiatric patients
  • Schizophrenia: prevalence rates of 70% in some surverys
    • Onset of symptoms earlier in drug-abusing schizophrenics
epidemiology1
Epidemiology
  • Schizophrenia: substance abuse associated with higher rates of homelessness, non-compliance, medical illness and violence
  • Bipolar disorder: rates estimated to be 50-70%
    • Associated with worse prognosis
epidemiology2
Epidemiology
  • Unipolar depression: 30-50%
    • Associated with treatment resistance and greater severity
    • Worsens alcohol dependence treatment outcomes
epidemiology3
Epidemiology
  • ADHD: NIDA estimates up to 50% of substance abuse patients
    • Increased risk of SUD up to 9 times
    • Effective childhood treatment reduces risk
epidemiology4
Epidemiology
  • PTSD: increased risk of SUD
    • Hypothalamic and noradrenergic mechanisms
    • PTSD precedes SUD
    • Substance abuse modifies neurobiologic substrate, intensifying PTSD symptoms which in turn intensify SUD
slide12
PTSD
  • In course of use, drug abusers place selves in dangerous situations
  • Withdrawal symptoms overlap with arousal symptoms
  • Increased CRH sensitizes LC, increasing noradrenergic tone which increases CRH release
  • Increased CRH by both substance abuse and PTSD potentiate fear responses in amygdala
epidemiology nicotine
Epidemiology - Nicotine
  • Nicotine-dependent patients with comorbid disorders: 7.1% US population consume 34.2% of all cigarettes smoked
havassy et al ajp 1 2004
Havassy et al. AJP 1/2004
  • Comparison study of comorbid patients recruited in two treatment settings
    • Residential (non-hospital) psychiatric for seriously mentally ill patients
    • Equivalent Substance abuse residential program
havassy et al
Havassy et al.
  • Of 420 eligible patients, 54% (N=226) met comorbid criteria
  • More MI patients met comorbid criteria than did SA (60%-49%)
cloninger s personality typology
Cloninger’s personality typology
  • Reward dependence
  • Harm avoidance
  • Novelty seeking
covariation of risk behaviors
Covariation of risk behaviors
  • % Sex TobAlcMJ
  • Sex: 100 83 88 74
  • Tobacco: 45 100 92 67
  • Marijuana: 56 94 95100
family risk factors
Family risk factors
  • Tarter 1999: developmental window: father stops use:
    • Before age 6 - child=control in sud and asp
    • After age 6 - no decrease in later sud
culture
Culture
  • Role of factors promoting or inhibiting use
    • Age
    • Gender
    • Ethnicity
  • Protective cultural boundaries
women and injection drug abuse
Women and injection drug abuse
  • Sexual and/or physical abuse significant risk factor for initiation and maintenance
  • NYC study:
    • 39% sexually abused before 16
    • 27% before 13
women and injection drug abuse1
Women and injection drug abuse
  • Women much more likely to have psychiatric diagnoses
  • NYC study: 65% women in methadone maintenance therapy have been abused as adults
  • Differences in needle-sharing behavior
havassy et al1
Havassy et al
  • No significant differences in overall rates of mental disorders
  • Higher prevalence of schizophrenic spectrum disorders in MI setting (43%-31%)
  • No signficant difference in bipolar prevalence
havassy et al2
Havassy et al
  • SA setting: decreased likelihood of suicide and psychiatric hospitalization history
  • No significant differences in rates of substance abuse
    • Severity of SA higher in SA setting
havassy et al3
Havassy et al
  • SA prevalence
    • Less opiate and cocaine use in schizophrenic patients
    • No difference in days of use

More similarities than

differences in two settings

self medication hypothesis
Self-medication hypothesis
  • Evidence nicotine attenuates stress reactivity
  • Schizophrenia: use nicotine to deal with negative symptoms: sleep, dysphoria, antipsychotic adverse effects and to improve cognitive function
neurobiology
Neurobiology
  • Drugs of abuse interact and alter neural substrates related to the pathobiology of psychiatric disorders
  • More neuropsychologic impairment
substance augmentation
Substance augmentation
  • Koob: ‘feed-forward system’ increases stress reactivity
  • Withdrawal states
  • Problem-solution interaction
neurotransmitters
Neurotransmitters
  • Dopamine
  • Opioids
  • Glutamate
  • GABA
  • Cannabinoids
  • Norepinephrine
dopamine
Dopamine
  • Neurotransmitter - a chemical messenger
  • Levels increase in the reward center when animals do those behaviors which ensure survival
  • D2 receptor: knockout mice
dopamine and anticipation
Dopamine and Anticipation
  • Dopamine levels increase in response to cue
  • If reward not presented, dopamine levels decrease
  • Decreased dopamine causes dysphoria
  • Example: drug cue but no drug leads to dysphoria and increased drive to obtain the drug
dopamine and withdrawal
Dopamine and Withdrawal
  • Decreased D2 receptors in withdrawal persisting for months
  • Plays mediating role in drug craving and drug seeking, dysphoria and relapse
opioids
Opioids
  • Three major receptor subtypes: mu, kappa, delta
  • Mu key to opiate addiction Knockout mice: no morphine dependence or withdrawal
  • Neuroimaging: increased mu receptors in abstinence
    • Craving results
opioids1
Opioids
  • Kappa stimulation decreases dopamine function in the NA resulting in dysphoria
  • Dynorphin is a kappa agonist
  • Buprenorphine is a kappa antagonist
glutamate
Glutamate
  • Prinicpal excitatory neurotransmitter
  • Pathways from the prefrontal cortex and amygdala project to NA
  • Plays role in reinstatement of drug-seeking behavior
glutamate1
Glutamate
  • NMDA receptor implicated in multiple addictions:
    • Alcohol
    • Nicotine
    • Cannabinoids
    • Cocaine
    • Amphetamine
    • Opioids
glutamate2
Glutamate
  • NMDA receptors upregulated in addiction as well as in chronic pain states
  • NMDA receptor antagonists decrease sensitization and craving
slide48
GABA
  • Principle inhibitory neurotransmitter
  • GABA-benzodiazepine receptor
  • Benzodiazepines only class of drugs of abuse that don’t increase dopamine
  • GHB activates GABA complex
  • GABA tone decreased with alcohol and opioid dependence
cannabinoids
Cannabinoids
  • Two receptors: CB1 (Brain) and CB2 (immune)
  • Activation: inhibits GABA leading to increase in dopamine in NA
  • Share properties with opioids
    • anti-nociception
    • sedation
definition
Definition
  • “Addiction is a cycle of spiraling dysregulation of brain reward systems that progressively increases, resulting in compulsive drug use and a loss of control over drug taking” George Koob
genetics
Genetics
  • No single gene
  • 40% genetic
  • Cloninger’s twin study
  • COGA
pathophysiology
Pathophysiology
  • Neural circuitry of reward and brain reward thresholds
  • Tolerance
  • Altered hedonic tone
  • Sensitization
  • Activation of HPA axis
  • Genetic predisposition
neural circuitry of reward
Neural circuitry of reward
  • Present in all animals
  • Produces pleasure for behaviors needed for survival:
  • Eating
  • Drinking
  • Sex
  • Nurturing
all drugs abuse increase dopamine in the nucleus accumbens
alcohol

cocaine

heroin

marijuana

nicotine

amphetamines

sedatives

hallucinogens

pcp

caffeine

All drugs abuse increase dopamine in the nucleus accumbens
drugs of abuse hijack the reward center
Drugs of abuse hijack the Reward Center
  • Instead of eating, drinking and making love, drugs tell you that you need to take them in order to survive.
  • This is obviously a lie, and one that leads to sickness and death.
neuroadaptation
Neuroadaptation
  • drugs change the brain’s balance
  • the brain has mechanisms to oppose this change
  • the balancing action ‘overshoots’:
  • the stronger the drug, the higher the dosage and the longer the use, the more the opposing change
neuroadaptation alcoholics drink
Neuroadaptation - alcoholics drink:
  • To get high
  • To get sedated
  • To get numb
neuroadaptation alcohol
Neuroadaptation: alcohol
  • High Depressed
  • Sedated Anxious/sleepless
  • Numb Anguish/pain
neuroadaptation alcoholics drink1
Neuroadaptation:Alcoholics drink:
  • To get high
  • To get sedated
  • To get numb
neuroadaptation alcohol1
Neuroadaptation: alcohol
  • High Depressed
  • Sedated Anxious/sleepless
  • Numb Anguish/pain
positive reinforcers
Positive reinforcers
  • Euphoria
  • Sedation
  • Anesthesia (numbing)
negative reinforcers
Negative reinforcers
  • Depression
  • Anxiety
  • Insomnia
  • Boredom
  • Loss of pleasure
neuroadaptation alcohol2
Neuroadaptation - Alcohol

The brain on grain falls mainly in the pain.

neuroadaptation opioids
Neuroadaptation: opioids
  • To get high
  • To get sedated
  • To get numb
neuroadaptation cocaine
Neuroadaptation - cocaine
  • Cocaine addicts use cocaine
  • To get high
  • To get high
  • To get high
neuroadaptation cocaine1
High

High

High

Depressed

Depressed

Depressed

Neuroadaptation: Cocaine
allostasis
Allostasis
  • change to new, vulnerable state
  • deficit states: inhibition of brain reward circuitry
  • altered hedonic tone (Koob)
  • reward thresholds increase
  • opponent process theory
  • counteradaptive hedonic dysregulation
alcohol
Alcohol:

Intoxication

Sober: 30 days

cannabis
Cannabis
  • Prospective studies demonstrate increased risk:
    • Schizophrenia
    • Major depressive disorder
    • Anxiety disorders, including panic
volkow methamphetamine
Volkow: methamphetamine
  • Persistent reductions in dopamine transport in striatum
  • Long-term psychomotor impairment
mdma ecstacy
MDMA – Ecstacy
  • Raves
  • Neurotoxic to serotonin neurons
  • Both animal model and now human findings
conditioning
Conditioning
  • Ivan Pavlov
  • Conditioned dogs to salivate when they heard a bell
  • 7-11
amygdala
Amygdala
  • Emotional responses
  • Filters all incoming sensations
  • Identifies both high risk and high pleasure stimuli
  • Very rapid response
brain organization1
Brain organization
  • The right brain thinks with images, not words
  • There is no DON’T ELEPHANT in the right brain
  • DON’T ELEPHANT= ELEPHANT!!
medications
Medications
  • Naltrexone (revia)
  • Topiramate
  • Acamprosate
  • Methadone
  • Buprenorphine
  • Bupropion
antabuse disulfiram
Antabuse (disulfiram)
  • Can cause severe reactions
  • Risks of hepatotoxicity, neuropathy
  • Lack ofdouble-blind studies
  • New use: cocaine craving
methadone
Methadone
  • Abstinence rates: 70-80%
  • Blocks craving
  • Blocks euphoria
  • Normalization of HPA axis
  • Normalization of limbic function
methadone1
Methadone
  • High rates of major depressive disorder and anxiety disorders
  • Treatment research:
    • Tricyclic antidepressants, SSRI’s and CBT effective
    • Methadone supports treatment compliance over active using condition
buprenorphine naloxone suboxone
Buprenorphine/naloxone: Suboxone
  • Partial agonist + pure antagonist
  • t/2 >24 hours
  • Blocks craving and euphoria
  • Less physical dependence
  • Combo decreases diversion risk
suboxone
Suboxone
  • DATA 2000: can be prescribed by office-based physicians
  • DEA waiver
  • 30 patient limit
  • Adolescent/young adults
  • September 2004 training
therapeutic effects
Therapeutic effects
  • blocking effect on euphoria with administration of heroin
  • blocking effect on withdrawal.
  • relieves craving
  • stabilization of brain function:
  • decrease in HPA stress state
  • improvement in mood and
  • behavioral stability
revia naltrexone
Revia - Naltrexone
  • Pure opioid antagonist
  • Effective in treatment of alcoholism and opiate addiction
  • Blocks craving
  • Blocks the ‘high’ and increases the negatives
acamprosate campral
Acamprosate - Campral
  • NMDA receptor antagonist
  • Blocks craving
  • Doubles abstinence rates
  • Additive with naltrexone
topiramate
Topiramate
  • Anti-convulsant
  • Anti-craving agent for alcohol, cocaine and cannabis
  • Increases alcohol abstinence rates by 50%
  • Patients reports enhanced sense of well-being
zyban bupropion
Zyban (bupropion)
  • Antidepressant
  • decreases craving
  • decreases withdrawal
  • can increase abstinence rates
  • side effects: GI, anxiety, headaches
summary
Summary
  • Addictive disorders are treatable brain diseases
  • Research is edifying the biological mechanisms involved
  • Increased understanding of neurobiology is allowing for the development of effective, targeted pharmacotherapies
summary1
Summary
  • An understanding of the neurobiology of addiction:
    • Destigmatizes both the patient and the treatment
    • Helps everyone understand the ‘why’ and the ‘how’ of otherwise baffling symptoms