understanding addiction from the inside...

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Understanding Addiction Understanding Addiction from the Inside Out from the Inside Out

Edwin A. Salsitz, M.D., FASAMEdwin A. Salsitz, M.D., FASAMBeth Israel Medical CenterBeth Israel Medical Center

NYCNYC

ADDICTION TREATMENTADDICTION TREATMENT

““AllAll Treatments Work For Treatments Work For SomeSomePeople/Patients”People/Patients”

““No OneNo One Treatment Works for Treatment Works for AllAllPeople/Patients” People/Patients”

Alan I. Leshner, Ph.DFormer Director NIDA

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Why Physicians are UnpreparedWhy Physicians are UnpreparedMiller, Miller, Academic Medicine Academic Medicine 2001:7:4102001:7:410--418418•• 12 hours of curricular time in avg.med.sch.12 hours of curricular time in avg.med.sch.•• Do not: 1. feel competent 2.like the patient Do not: 1. feel competent 2.like the patient p pp p

3.feel rewarded 4.have role models3.feel rewarded 4.have role models•• Barriers Identified:Barriers Identified:

1.Lack of acceptance of medical model1.Lack of acceptance of medical model2.Lack of faculty/physician role models2.Lack of faculty/physician role models3 C i l d fi it i h l/ id3 C i l d fi it i h l/ id3.Curricular deficits in school/residence3.Curricular deficits in school/residence4.Lack of parity and physician advocacy4.Lack of parity and physician advocacy5.Personal/family hx. of addictive disease5.Personal/family hx. of addictive disease

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Depends How You Look at Things?

What Is Addiction?What Is Addiction?

You Never Do What Addicted You Never Do What Addicted P l D O D Y ??P l D O D Y ??People Do…..Or Do You??People Do…..Or Do You??

ContinuumContinuumUserUser ---------------------------------- AddictedAddicted

VulnerabilityVulnerabilityUnderstandableUnderstandable

Logical, Rational, LinearLogical, Rational, Linear

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What is Addiction?What is Addiction?

•• Chronic Brain DiseaseChronic Brain DiseaseChronic Brain DiseaseChronic Brain Disease•• Generally ProgressiveGenerally Progressive•• Not CurableNot Curable——”Recovering””Recovering”•• Exacerbations(Relapses) & RemissionsExacerbations(Relapses) & Remissions•• TreatableTreatable------many modalities(evidence base)many modalities(evidence base)•• TreatableTreatable------many modalities(evidence base)many modalities(evidence base)•• Multidisciplinary TeamMultidisciplinary Team

What Is Addiction?What Is Addiction?

•• Continued Use of an Activity DespiteContinued Use of an Activity DespiteContinued Use of an Activity, Despite Continued Use of an Activity, Despite Knowledge of Continued Harm to One’s Knowledge of Continued Harm to One’s Self or OthersSelf or Others------”Use Despite Harm””Use Despite Harm”

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ADDICTIONADDICTION——TOWER of BABELTOWER of BABEL

•• BA/BSBA/BS•• MPH/MBAMPH/MBA

•• CASAC, counselorsCASAC, counselors•• Clergy, SpiritualClergy, Spiritual//

•• CSW/MSWCSW/MSW•• MD’sMD’s——variousvarious•• Ph.DPh.D——variousvarious•• RN/NP/LPNRN/NP/LPN•• PAPA

gy, pgy, p•• PoliticiansPoliticians•• Lawyers, JudgesLawyers, Judges•• Criminal Justice CourtCriminal Justice Court•• Probation/ParoleProbation/Parole•• AdministratorsAdministratorsPAPA

•• Comp/AltComp/Alt•• Patient AdvocatesPatient Advocates

AdministratorsAdministrators•• RegulatorsRegulators•• Almost AnyoneAlmost Anyone

Staff members in Recovery or Not

ADDICTION/HEALTH CARE ADDICTION/HEALTH CARE PROVIDERPROVIDER

S lfS lf i fli t di fli t d •• Medical diseasesMedical diseases•• SelfSelf--inflictedinflicted

•• Futile treatmentFutile treatment

•• WithdrawalWithdrawal

•• IntoxicationIntoxication

•• Medical diseasesMedical diseases

•• The “other”The “other”

•• AMAAMA

•• 2 a.m. admission2 a.m. admission

•• B lli tB lli t•• TraumaTrauma

•• Taking advantageTaking advantage

•• BelligerentBelligerent

•• DestitutionDestitution

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What is Addiction? (1)What is Addiction? (1)(descriptive)(descriptive)

•• An activity which initially provides pleasure, An activity which initially provides pleasure, and is and is relatively, and usuallyrelatively, and usually harmlessharmless

•• Increases Hedonic ToneIncreases Hedonic Tone•• De gustibus non disputandum De gustibus non disputandum •• The vulnerable recognize relief of dysphoric The vulnerable recognize relief of dysphoric

feelings, and often report feeling “normal”feelings, and often report feeling “normal”

What is Addiction? (1)What is Addiction? (1)(neuro(neuro--biology)biology)

•• An activity which initially stimulates the An activity which initially stimulates the “limbic” system, which results in changes “limbic” system, which results in changes of neurotransmitter levels, which are of neurotransmitter levels, which are perceived as euphoria (perceived as euphoria ( hedonic tone)hedonic tone)perceived as euphoria (perceived as euphoria ( hedonic tone)hedonic tone)

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Bungee Cord Jumping

BAC=0.432 mg. % (0.08)

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7/10/09

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Why People Use DrugsWhy People Use Drugs

•• To Alter MoodsTo Alter MoodsTo Alter MoodsTo Alter Moods•• To Promote and Enhance Social InteractionsTo Promote and Enhance Social Interactions•• To Enhance Sensory Experience and PleasureTo Enhance Sensory Experience and Pleasure•• To Aid Religious PracticesTo Aid Religious Practices•• To Explore the SelfTo Explore the Self•• To Explore the SelfTo Explore the Self•• To Stimulate Artistic CreativityTo Stimulate Artistic Creativity•• To RebelTo Rebel

Weil, From Chocolate to Morphine, 1993

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What is Addiction?What is Addiction?

1.1. AbstinentAbstinent

Agent UsageAgent Usage

2.2. Use Use –– social, religioussocial, religiouscircumstantial (medical)circumstantial (medical)experimentalexperimentaloperationaloperationalrecreationalrecreational

HHAARR

3.3. Abuse / MisuseAbuse / Misuse4.4. AddictionAddiction5.5. Legal / IllegalLegal / Illegal

MM

Reward Pathways

Frontal Cort.

VTANuc. Acc.

Frontal Cort.

DA pathways

11

Acc VTA

FCXAMYG

GLU HIPP

AmphetamineCocaineOpiatesCannabinoidsPhencyclidineKetamineCRF

VP

ABN LC

GABA

ENK OPIOIDGABA

GABA

GABA

DYN

5HT

5HT

NE

DA

GLU

OPIOID

BNSTOFT

ABN

Raphé

LC

5HT

PAG

RETIC

To dorsalhorn

ENDOpiates

ICSSOpiatesEthanolBarbituratesBenzodiazepinesNicotineCannabinoids

HYPOTHALLAT-TEG

NE

MesoLimbic Dopaminergic Circuit Pleasure/Reward CenterH2O, Food, Sex, Parenting, Social

The NeuroChemical Output of The NeuroChemical Output of the “Limbic System” sets the the “Limbic System” sets the organism’sorganism’s Hedonic ToneHedonic Toneorganism s organism s Hedonic ToneHedonic Tone

Feelings and Emotions are Feelings and Emotions are Neurochemical ReactionsNeurochemical Reactions

Neurochemical Reactions produceFeelings and Emotions

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HEDONIC TONEHEDONIC TONE•• Sense of well being, happiness, pleasure, Sense of well being, happiness, pleasure,

contentmentcontentment•• “S t” b /i th li bi d i i“S t” b /i th li bi d i i•• “Set” by/in the mesolimbic dopaminergic “Set” by/in the mesolimbic dopaminergic

circuitry(Pleasure/Reward/Survival Center)circuitry(Pleasure/Reward/Survival Center)•• Range: Euphoria Range: Euphoria -- DysphoriaDysphoria•• Altered by Psychoactive ActivitiesAltered by Psychoactive Activities•• A Delicate BalanceA Delicate Balancee ca e a a cee ca e a a ce•• Human ConditionHuman Condition•• (?abnormal tone in the vulnerable, prior to (?abnormal tone in the vulnerable, prior to

the addictive state)the addictive state)

HEDONIC TONE SOURCESHEDONIC TONE SOURCES•• SAFESAFE•• DURABLEDURABLE•• PRODUCTIVEPRODUCTIVE•• DEPENDABLE DEPENDABLE

e.g. family, work, education, petse.g. family, work, education, pets

&&&&*Appropriate FUN & EUPHORIA*Appropriate FUN & EUPHORIA

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Man dives in to save dog from Fla. shark attack

The Fla. man punches 5-foot shark until it lets go of his rat terrier Jake

"I thought Jake deserved whatever I could do," LeNoir said of his heroism. 9/30/08

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IS X POTENTIALLY ADDICTIVE?IS X POTENTIALLY ADDICTIVE?•• Must Activate the Hedonic Tone CircuitsMust Activate the Hedonic Tone Circuits•• Water(psychogenic polydipsia)Water(psychogenic polydipsia)•• Water(psychogenic polydipsia)Water(psychogenic polydipsia)•• FoodFood——Obesity EpidemicObesity Epidemic•• SexSex•• ExerciseExercise•• Is Alcohol Addictive??Is Alcohol Addictive?? Only if VulnerableOnly if VulnerableIs Alcohol Addictive??Is Alcohol Addictive?? Only if VulnerableOnly if Vulnerable•• Is Penicillin Addictive??Is Penicillin Addictive?? NoNo•• So, like a Shakespearen tragic flaw, a So, like a Shakespearen tragic flaw, a

virtue taken to excess.virtue taken to excess.

500500600600700700800800900900

1000100011001100

Bas

al R

elea

seB

asal

Rel

ease

DADADOPACDOPACHVAHVA

AccumbensAccumbens AMPHETAMINEAMPHETAMINE

200200

300300

400400

asal

Rel

ease

asal

Rel

ease

DADADOPACDOPACHVAHVA

AccumbensAccumbensCOCAINECOCAINE

Effects of Drugs on Dopamine LevelsEffects of Drugs on Dopamine LevelsEffects of Drugs on Dopamine LevelsEffects of Drugs on Dopamine Levels

00100100200200300300400400500500

00 11 22 33 44 5 hr5 hrTime After AmphetamineTime After Amphetamine

% o

f %

of

00

100100

200200

00 11 22 33 44 5 hr5 hrTime After CocaineTime After Cocaine

% o

f Ba

% o

f Ba

200200

250250

ease

ease

AccumbensAccumbens

NICOTINENICOTINE

200200

250250

ee

AccumbensAccumbens

Dose (g/kg ip)Dose (g/kg ip)

ETHANOLETHANOLETHANOLETHANOL

00

100100

150150

00 11 22 3 hr3 hrTime After NicotineTime After Nicotine

% o

f Bas

al R

ele

% o

f Bas

al R

ele AccumbensAccumbens

CaudateCaudate

Source: Di Chiara and ImperatoSource: Di Chiara and Imperato

100100

150150

200200

00 11 22 33 4hr4hrTime After EthanolTime After Ethanol

% o

f Bas

al R

elea

s%

of B

asal

Rel

eas

0.250.250.50.5112.52.5

00

Dose (g/kg ip)Dose (g/kg ip)

15

200200NAc shellNAc shell

FOODFOOD200200

asel

ine)

asel

ine)

SEXSEX

Natural Rewards Elevate Dopamine Natural Rewards Elevate Dopamine LevelsLevels

Natural Rewards Elevate Dopamine Natural Rewards Elevate Dopamine LevelsLevels

00

5050

100100

150150

% o

f Bas

al D

A O

utpu

t%

of B

asal

DA

Out

put

EmptyEmptyBoxBox FeedingFeeding

100100

150150

DA

Con

cent

ratio

n (%

Ba

DA

Con

cent

ratio

n (%

Ba

1515

00

55

1010

Copulation Frequenc

Copulation Frequenc

0000 6060 120120 180180

Time (min)Time (min)

Source: Di Chiara et al.Source: Di Chiara et al.

MountsMountsIntromissionsIntromissionsEjaculationsEjaculations

00 cycy

SampleNumberSampleNumber

11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414 1515 1616 1717

ScrScrScrScrBasBasFemale 1 PresentFemale 1 Present

ScrScrFemale 2 PresentFemale 2 Present

ScrScr

Source: Fiorino and PhillipsSource: Fiorino and Phillips

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TOBACCO ADDICTION: 1PPD X 20YEARS8 Puffs/Cigarette

160 Puffs/Day1170 Puffs/Week

33,600 Puffs/Month403,700 Puffs/Year

8,064,000 Puffs/20 YearsCompare frequency/repetition of administration to any other addictionCompare frequency/repetition of administration to any other addictionHabitual behavior?Duration of effective pharmacological treatment: 12wks. 24wks. ??

LIMBIC SYSTEM(pleasure/reward center)Gender Differences

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LIMBIC SYSTEM---MALE/FEMALE

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“Pleasure” Phase Ends for the VulnerableRemains for “Social/Recreational” Use

NAshellNA

shell

vPFCvPFC

mVPmVP

VTAVTA

Reward – Limbic Subcircuit


•• In those who are vulnerableIn those who are vulnerable------family history, family history, and “life narrative”/environmentand “life narrative”/environment------ the the frequency, potency, method/route, and frequency, potency, method/route, and salience of the activity increases, the salience of the activity increases, the pleasure/hedonic tone decreasespleasure/hedonic tone decreases, and, andpleasure/hedonic tone decreasespleasure/hedonic tone decreases, and , and the the harm increasesharm increases..

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•• In the vulnerable, as the stimulation to In the vulnerable, as the stimulation to the limbic and other parts of the brain the limbic and other parts of the brain continue, perturbations in brain continue, perturbations in brain function result in dysphoria, function result in dysphoria, y p ,y p ,withdrawal, and impairments.withdrawal, and impairments.

Hedonic Tone

THE ALCOHOLICTHE ALCOHOLICBy Jonathan Ames; illustrations by Dean HaspielBy Jonathan Ames; illustrations by Dean Haspiel

•• The answer begins in 1979, when Jonathan, a high The answer begins in 1979, when Jonathan, a high g , , gg , , gschool sophomore, discovered the magical effects of school sophomore, discovered the magical effects of beer: “I didn’t care about the taste. I loved the way it beer: “I didn’t care about the taste. I loved the way it made me feel. For the first time in my life, I felt cool. I made me feel. For the first time in my life, I felt cool. I had always thought I was ugly, but not that night.” had always thought I was ugly, but not that night.”

•• After that initial experience, Jonathan gets drunk every After that initial experience, Jonathan gets drunk every weekend for two years, with his best friend, Sal. But it’s weekend for two years, with his best friend, Sal. But it’s y , ,y , ,not all fun, games and beer. One page captures the not all fun, games and beer. One page captures the highs and lows: drinking lazily by a pond and hitting keg highs and lows: drinking lazily by a pond and hitting keg parties, juxtaposed with vomiting in the woods and parties, juxtaposed with vomiting in the woods and blacking out in bed.blacking out in bed.

Book Review, NYT, 10/15/08

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Vulnerability to AddictionVulnerability to Addiction•• GeneticGenetic•• EnvironmentalEnvironmental•• CulturalCultural•• StressStress•• Spotlight EuphoriaSpotlight Euphoria•• GeriatricsGeriatrics•• AdolescentsAdolescents•• DestitutionDestitution•• AvailabilityAvailability

Genetic Protection

ALDH. Several isozymes of ALDH have been identified, but only the cytosolic ALDH1ALDH. Several isozymes of ALDH have been identified, but only the cytosolic ALDH1 and the mitochondrial ALDH2 metabolize acetaldehyde. There is one significant genetic polymorphism of the ALDH2 gene, resulting in allelic variants ALDH2*1 and ALDH2*2, which is virtually inactive. ALDH2*2 is present in about 50 percent of the Taiwanese, Han Chinese, and Japanese populations (Shen et al. 1997) and shows virtually no acetaldehyde metabolizing activity in vitro. People who have one (i.e., heterozygous) or especially two (i.e., homozygous) copies of the ALDH2*2 allele show increased acetaldehyde levels after alcohol consumption (Luu et al. 1995; Wall et al. 1997) and therefore experience negative physiological responses to alcohol.

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Addiction and CultureAddiction and Culture

•• Stroke of MidnightStroke of Midnight——20th20th 21st Birthday21st BirthdayStroke of MidnightStroke of Midnight 20th20th 21st Birthday21st Birthday•• POWER HOURPOWER HOUR——”21 for 21””21 for 21”--Bar Closes 2AMBar Closes 2AM

•• “After 30 minutes and the 13“After 30 minutes and the 13thth shotshot--a Prairie a Prairie Fire, or Tequila with Fire, or Tequila with TabascoTabasco-- he vomits into a he vomits into a metal bucket, provided by the bar, the birthday metal bucket, provided by the bar, the birthday souvenir taken home. Then he resumes souvenir taken home. Then he resumes drinking.”drinking.”

•• “It’s the best time of his life,” a friend slurs to “It’s the best time of his life,” a friend slurs to the camera.”the camera.”

•• Deaths in CA. MI. NM. ND. RI. TX. Deaths in CA. MI. NM. ND. RI. TX. NYTNYT——2/052/05--NDND

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Research in rhesus monkeys suggests that good mothering may buffer thedeleterious effects of a genetic variant in offspring that has been linked to behavioral problems. JAMA. 2006;295:1756-1760

Addiction VulnerabilityAddiction VulnerabilityGene/Enviroment InteractionGene/Enviroment Interaction•• Monkeys with short 5Monkeys with short 5--HTT variant who were HTT variant who were

d h d d fi it i t i td h d d fi it i t i tpeerpeer--reared had deficits in serotonin met. reared had deficits in serotonin met. •• Monkeys with long 5Monkeys with long 5--HTT variant who were HTT variant who were

peerpeer--reared had elevated serotonin met.reared had elevated serotonin met.•• MotherMother--reared monkeys all had normal reared monkeys all had normal

serotonin met whether short/long 5serotonin met whether short/long 5--HTTHTTserotonin met. whether short/long 5serotonin met. whether short/long 5 HTTHTT•• Aggression in PAggression in P--R, but not MR, but not M--R shortR short•• Low aggression in long, PLow aggression in long, P--R or MR or M--RR

Suomi, JAMA,2006, 295:1759

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Fig. 6Fig. 6

•• Volkow et al., May 2003Volkow et al., May 2003

24

Fig. 2Fig. 2

•• Volkow et al., 2003Volkow et al., 2003

Nature Neuroscience 5, 169 - 174 (2002)

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PET Images:PET Images:Dopamine Receptor DensityDopamine Receptor Density

Social Dominance in Monkeys: Dopamine Receptors and Cocaine Self-AdministrationMorgan et al, Nature Neuroscience 2002

Effect of Social Dominance on CocaineEffect of Social Dominance on CocaineSelf Self --AdministrationAdministration

2.02.0 TOTAL INTAKE

(mg/kg/session)

TOTAL INTAKE

(mg/kg/session)))

*

*

0.50.5

1.01.0

1.51.5

(mg/kg/session)(mg/kg/session)

SubordinateSubordinatentak

e/se

ssio

n (m

g/kg

ntak

e/se

ssio

n (m

g/kg

.003.003 .01.01 .03.03 .1.1

0.00.0

Cocaine (mg/kg/injection)Cocaine (mg/kg/injection)

Subordinate

Dominant

Subordinate

DominantMea

n in

Mea

n in

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It's Good to Be the King!

Watch Your Back

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DestitutionDestitution

•• Lacking something neededLacking something neededLacking something neededLacking something needed•• Lacking possessions and resourcesLacking possessions and resources•• Suffering extreme wantSuffering extreme want•• Such extreme want as threatens life Such extreme want as threatens life

unless relievedunless relievedunless relievedunless relieved•• Disconnected from societyDisconnected from society•• “Chaotic”“Chaotic”

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DESTITUTION & ADDICTIONDESTITUTION & ADDICTION•• HousingHousing--HomelessHomeless•• Family & FriendsFamily & Friends

Ed tiEd ti

•• Medical CoMedical Co--morbiditymorbidity•• Psychiatric DisordersPsychiatric Disorders

HIV/AIDSHIV/AIDS•• EducationEducation•• LiteracyLiteracy•• Vocational SkillsVocational Skills•• EmploymentEmployment•• FinancesFinances

•• HIV/AIDSHIV/AIDS•• Criminal JusticeCriminal Justice•• Racial IssuesRacial Issues•• Societal AttitudesSocietal Attitudes•• Despair, HopelessDespair, Hopeless

•• WelfareWelfare•• Abuse Abuse •• SpiritualitySpirituality

•• Civility,Anger,GratitudeCivility,Anger,Gratitude•• Societal InstitutionsSocietal Institutions•• AddictionsAddictions

The Whole is Greater than the Sum of its Parts

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ADDICTION VOCABULARY

Slang Medical

Addict Addicted patient, patient with the disease of addiction

Junkie , dope fiend Opiate addicted patient, cocaine addicted patient

Cl i U i ti f illi it ib d dClean urine Urine negative for illicit or non-prescribed drugs

Dirty urine Urine pos itive for x,y,or z

Drunk, smashed, bombed Alcohol addicted, intoxicated

Crack head, pot head Cocaine addicted, THC abuse

La La Land Intoxicated

Street addict, hard-core addict Patient with the disease of addiction

Speed-balling Us ing heroin and cocaine togetherp g g g

Meth Methadone or Methamphetamine

Strung out Debilitated, intoxicated

Cop/Fix Obtain, purchase /Dosed, took

Hooked Addicted

Kicking Withdrawal Syndrome

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New York Times

Dry Mouth Decay, Crave Sugary Drinks, Brushing/Flossing, Caustic IngredientsGrinding/Clenching Teeth,

33

Dopamine Transporter Loss AfterHeavy Methamphetamine Use

Comparison Subject METH Abuser

Volkow N. D. et al., Am.J. Psychiatry 158(3), pp. 377-382, 2001

Dependence of Verbal Memory on Dependence of Verbal Memory on Striatal DATStriatal DATDependence of Verbal Memory on Dependence of Verbal Memory on Striatal DATStriatal DAT

15

s

15

s

Interference RecallInterference RecallInterference RecallInterference Recall Delayed recallDelayed recallDelayed recallDelayed recall

3

6

9

12

Num

ber

of w

ords

3

6

9

12

Num

ber

of w

ords

R = 0.70R = 0.70p < 0.005p < 0.005R = 0.70R = 0.70p < 0.005p < 0.005

R = 0.64R = 0.64p < 0.01p < 0.01R = 0.64R = 0.64p < 0.01p < 0.01

01 1.2 1.4 1.6 1.8 2

Dopamine transporter (Bmax/Kd)

01 1.2 1.4 1.6 1.8 2

Dopamine transporter (Bmax/Kd)

. . Volkow N. D. et al., Am.J. Psychiatry 158(3), pp. 377-382, 2001

34

Different Brain Circuitry Involved inDrug Reward and Drug Persistance Behavior

Blockade in theseregions blocksrelapse ordopamine

NAshellNA

shell

vPFCvPFC

mVPmVP

VTAVTA

relapse orreinstatement

dopamine

NAcoreNAcore

dPFCdPFC

SNSN

dVPdVPglutamate

Source: Adapted from McFarland, K. and Kalivas, P.W. Journal of Neuroscience, 21(21), pp. 8655-8663, November 1, 2001.Source: Adapted from McFarland, K. and Kalivas, P.W. Journal of Neuroscience, 21(21), pp. 8655-8663, November 1, 2001.

Reward – Limbic Subcircuit

Drug Seeking Behavior – Motor Subcircuit


•• Attempts to abstain from the activity are Attempts to abstain from the activity are thwarted by cravings and “prolonged” thwarted by cravings and “prolonged” withdrawal syndromes.withdrawal syndromes.

•• Relapse is common, and often related to Relapse is common, and often related to d dd ddrug cues, stress, or drug exposure.drug cues, stress, or drug exposure.

35


A b b i h d bA b b i h d b•• Attempts to be abstinent are thwarted by Attempts to be abstinent are thwarted by the as yet illthe as yet ill--defined concepts of craving defined concepts of craving and prolonged withdrawal syndromes. The and prolonged withdrawal syndromes. The vulnerablity, which is not “curable,” may vulnerablity, which is not “curable,” may also play a role.also play a role.

d h l bd h l b•• Evidence suggests that relapse may be Evidence suggests that relapse may be mediated via glutamatergic, dopaminergic mediated via glutamatergic, dopaminergic HPA axis, amygdala, and hippocampal HPA axis, amygdala, and hippocampal mechanisms.mechanisms.

38

CRF1 Receptor Antagonist AttenuatesStress-Induced Reinstatement

of Drug Seeking

CRF1 Receptor Antagonist AttenuatesStress-Induced Reinstatement

of Drug SeekingAlcohol-trained ratsAlcohol-trained rats Heroin-trained ratsHeroin-trained rats Cocaine-trained ratsCocaine-trained rats

Intermittent Footshock Intermittent Footshock No stressNo stress

* *1515

3030

4545

6060

Res

pons

es (3

hr)

Res

pons

es (3

hr)

*

**

1515

3030

4545

6060

Res

pons

es (1

hr)

Res

pons

es (1

hr)

From: Shaham et al. Psychopharmacology 1998; Le et al. Psychopharmacology, 2000From: Shaham et al. Psychopharmacology 1998; Le et al. Psychopharmacology, 2000

CP-154,526 Dose (mg/kg, SC)CP-154,526 Dose (mg/kg, SC)

00 1515 303000

RR

00 1515 303000

RR

00 1515 3030

What Is Addiction? (4)What Is Addiction? (4)(descriptive)(descriptive)

•• Treatment is directed at improving, and Treatment is directed at improving, and maximizing function in the personal, maximizing function in the personal, vocational, educational, psychological, and vocational, educational, psychological, and spiritual aspects of the patient’s life.spiritual aspects of the patient’s life.

39


•• Treatment is directed at stabilizing, Treatment is directed at stabilizing, improving, and hopefully reversing the improving, and hopefully reversing the neurobiological perturbations secondary to neurobiological perturbations secondary to the addictive agent, and the underlying the addictive agent, and the underlying vulnerability(?psychiatric covulnerability(?psychiatric co--morbidity).morbidity).vulnerability(?psychiatric covulnerability(?psychiatric co morbidity).morbidity).

MEDICATION/PSYCHOSOCIAL

40

MEDICATION/PSYCHOSOCIAL

Psychiatry Research: NeuroimagingVolume 90, Issue 3 , 30 J 1999 P

Cerebral phosphorus metabolite abnormalities in

39 wks137 wks

30 June 1999, Pages 143-152Kaufman,M

opiate-dependent polydrug abusers in methadonemaintenance

Phosphorous MRSpectroscopy

Fig. 3. Metabolite levels in control subjects (n=16) and in short- (n=7) and long-term (n=8) methadone maintenance treatment (MMT) subgroups. Shown are means±S.D. of percent metabolite measures. Post hoc Scheffé test results: *P<0.05 vs. control subjects; **P<0.01 vs. control subjects; ***P<0.0001 vs. control subjects ;†P<0.05 vs. long-term MMT group

Spectroscopy

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From these data, we conclude that polydrug From these data, we conclude that polydrug abusers in MMT have 31Pabusers in MMT have 31P--MRS results consistentMRS results consistentabusers in MMT have 31Pabusers in MMT have 31P MRS results consistent MRS results consistent with abnormal brain metabolism and phospholipid with abnormal brain metabolism and phospholipid balance. The nearly normal metabolite profile in balance. The nearly normal metabolite profile in longlong--term MMT subjects suggests that prolonged term MMT subjects suggests that prolonged MMT may be associated with improved MMT may be associated with improved

neurochemistryneurochemistryneurochemistry.neurochemistry.

Psychiatry Research: NeuroimagingVolume 90, Issue 3 , 30 June 1999, Pages 143-152

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OPIOIDSOPIOIDS•• Methadone MaintenanceMethadone Maintenance•• Buprenorphine MaintenanceBuprenorphine Maintenance——s.l. tabs.s.l. tabs.•• Naltrexone tabletsNaltrexone tablets•• LAAMLAAM

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ALCOHOLALCOHOL

•• Disulfiram(Antabuse)Disulfiram(Antabuse)Disulfiram(Antabuse)Disulfiram(Antabuse)•• Naltrexone tablets(Revia)Naltrexone tablets(Revia)•• Acamprosate(Campral)Acamprosate(Campral)•• Naltrexone I.M. depot(Vivitrol)Naltrexone I.M. depot(Vivitrol)•• *Topiramate(Topimax)*Topiramate(Topimax)•• Topiramate(Topimax)Topiramate(Topimax)

TOBACCOTOBACCO

•• Nicotine Replacment TherapyNicotine Replacment TherapyNicotine Replacment Therapy Nicotine Replacment Therapy gum, patches, nasal spray, puffer, gum, patches, nasal spray, puffer, lozengelozenge

•• Bupropion(Zyban)Bupropion(Zyban)•• Varenicline(Chantix)Varenicline(Chantix)( )( )•• *Rimonabont*Rimonabont

44

COCAINECOCAINE

•• *Modafinil(Provigil)*Modafinil(Provigil)Modafinil(Provigil)Modafinil(Provigil)•• *Disulfiram(Antabuse)*Disulfiram(Antabuse)•• *Desimpramine*Desimpramine•• *Baclofen*Baclofen•• *Vaccine*Vaccine•• VaccineVaccine•• *Amphetamine*Amphetamine

Abstinence & AA meeting amountAbstinence & AA meeting amount

70

10203040506070

abst

inen

t mos

. 9-1

2

Moos et al., J Clin Psychol 2001

010%

0 1-19 20-49 50+# of meetings mos. 9-12

Male VA residential patientsn = 2376

understanding addiction from the inside...

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