Neurobiology of addiction
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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

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Neurobiology of addiction

Neurobiology of Addiction

Mark Publicker, MD FASAM

Medical Director

Mercy Recovery Center



  • 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


Anxiety disorders

Bipolar disorder





Axis II disorders

Co-morbid psychiatric disorders



  • 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



  • 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



  • Unipolar depression: 30-50%

    • Associated with treatment resistance and greater severity

    • Worsens alcohol dependence treatment outcomes



  • ADHD: NIDA estimates up to 50% of substance abuse patients

    • Increased risk of SUD up to 9 times

    • Effective childhood treatment reduces risk



  • 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

Neurobiology of addiction


  • 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

  • %SexTobAlcMJ

  • 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



  • 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

Nerve cells

Nerve cells

Synapse and neurotransmission

Synapse and neurotransmission

Dopamine neurotransmission

Dopamine neurotransmission

Dopamine and c amp

Dopamine and c-AMP

Dopamine receptors and reuptake pumps

Dopamine receptors and reuptake pumps

Cocaine binding to uptake pumps

Cocaine binding to uptake pumps

Pet scan brain on cocaine

PET scan: brain on cocaine

Opiates binding to opiate receptors in the na

Opiates binding to opiate receptors in the NA

Increased camp activity

Increased cAMP activity

Thc binding sites

THC binding sites

Thc binding increases dopamine release in na

THC binding increases dopamine release in NA

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



  • 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



  • Dopamine

  • Opioids

  • Glutamate

  • GABA

  • Cannabinoids

  • Norepinephrine



  • 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



  • Three major receptor subtypes:mu, kappa, delta

  • Mu key to opiate addictionKnockout mice: no morphine dependence or withdrawal

  • Neuroimaging: increased mu receptors in abstinence

    • Craving results



  • Kappa stimulation decreases dopamine function in the NA resulting in dysphoria

  • Dynorphin is a kappa agonist

  • Buprenorphine is a kappa antagonist



  • Prinicpal excitatory neurotransmitter

  • Pathways from the prefrontal cortex and amygdala project to NA

  • Plays role in reinstatement of drug-seeking behavior



  • NMDA receptor implicated in multiple addictions:

    • Alcohol

    • Nicotine

    • Cannabinoids

    • Cocaine

    • Amphetamine

    • Opioids



  • NMDA receptors upregulated in addiction as well as in chronic pain states

  • NMDA receptor antagonists decrease sensitization and craving

Neurobiology of addiction


  • 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



  • Two receptors: CB1 (Brain) and CB2 (immune)

  • Activation: inhibits GABA leading to increase in dopamine in NA

  • Share properties with opioids

    • anti-nociception

    • sedation



  • “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



  • No single gene

  • 40% genetic

  • Cloninger’s twin study

  • COGA



  • 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

Self stimulation studies

Self-stimulation studies

All drugs of abuse bind to the neural circuitry of reward

All drugs of abuse bind to the neural circuitry of reward

All drugs abuse increase dopamine in the nucleus accumbens











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.



  • 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







Neuroadaptation: Cocaine

Cocaine and mood changes

Cocaine and mood changes

Opponent process theory

Opponent process theory

Opponent process heroin

Opponent process - heroin



  • 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

Cocaine pet scan

Cocaine PET scan

Spect scan healthy brain top down and underside

SPECT scan: healthy brain top down and underside

Heroin spect scans

Heroin SPECT scans




Sober: 30 days



  • 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

Selective brain activation accompanies cocaine craving

Selective brain activation accompanies cocaine craving

Neutral Edythe London

Lateral prefrontal and visual cortex are activated edythe london

Lateral prefrontal and visual cortex are activated Edythe London

Limbic regions are activated during cocaine craving edythe london

Limbic regions are activated during cocaine craving Edythe London

Craving is correlated with activity in orbitofrontal cortex edythe london

Craving is correlated with activity in orbitofrontal cortex Edythe London



  • Ivan Pavlov

  • Conditioned dogs to salivate when they heard a bell

  • 7-11



  • Emotional responses

  • Filters all incoming sensations

  • Identifies both high risk and high pleasure stimuli

  • Very rapid response

Limbic conditioning

Limbic conditioning

Brain organization

Brain organization

Brain organization1

Brain organization

  • The right brain thinks with images, not words

  • There is no DON’T ELEPHANT in the right brain


Which step says don t drink

Which step says “Don’t drink”?

None of them



  • 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



  • Abstinence rates: 70-80%

  • Blocks craving

  • Blocks euphoria

  • Normalization of HPA axis

  • Normalization of limbic function



  • 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



  • 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



  • 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



  • 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



  • 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

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