Addictions and the Brain

Home , Amantadine, Disulfiram, Enadoline, Lobeline, Memantine

9/18/2012

TAAP Conference September 14, 2012

Acknowledgements

• La Hacienda Treatment Center • American Society of Addiction Medicine • National Institute of Drug Abuse

Definition

• A primary, progressive biochemical, psychosocial, genetically transmitted chronic disease of relapse who’s hallmarks are denial, loss of control and unmanageability.

DSM IV Criteria for dependency: At least 3 of the 7 below

1. Withdrawal 2. Tolerance 3. The substance is taken in larger amounts or over a longer period than was intended. 4. There is a persistent desire or unsuccessful efforts to cut down or control substance use. 5. A great deal of time is spent in activities necessary to obtain the substance, use the substance, or recover from its effects. 6. Important social, occupational, or recreational activities are given up or reduced because of the substance use. 7. The substance use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance.

Dispute between behavior and disease

Present understanding of the Hypothalamus location of the disease hypothesis.

Dispute regarding behavior versus disease

Natural Rewards Elevate Dopamine Levels

FOOD SEX 200 200 NAc shell

150 150 Copulation Copulation Frequency 100 100 15

Empty 10 50 Box Feeding

% of Basal DA Output Basal of DA % 5 DA Concentration Concentration (% Baseline) DA 0 0 0 60 120 180 ScrScr Scr Scr BasFemale 1 Present Female 2 Present Time (min) Sample 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Number Mounts Intromissions Ejaculations

Source: Di Chiara et al. Source: Fiorino and Phillips

Effects of Drugs on Dopamine Levels

Accumbens COCAINE 1100 AMPHETAMINE Accumbens

1000 400

900 800 DA DA 300 700 DOPAC DOPAC HVA 600 HVA 500 200 400

% ofReleaseBasal % 300 200 ofReleaseBasal % 100 100 0 0 1 2 3 4 5 hr 0 0 1 2 3 4 5 hr Time After Amphetamine Time After Cocaine

250 NICOTINE Accumbens MORPHINE 250 Dose (mg/kg) 200 Accumbens 200 0.5 Caudate 1.0 150 2.5 150 10 100

100

% ofReleaseBasal % % ofReleaseBasal %

0 0 1 2 3 hr 0 0 1 2 3 4 5hr Time After Nicotine Time After Morphine Source: Di Chiara and Imperato

Striatal FDOPA Activity

Pre-Amphetamine/Control

Post-Chronic Amphetamine (10 days)

4 weeks

6 months

1 year

2 years

Superior Inferior

Dopamine Transporters in Methamphetamine Abusers

2.4

2.2

2.0

1.8

Normal Control 1.6

1.4 (Bmax/Kd) 1.2

Dopamine Transporters Dopamine 1.0 Normal Meth Controls Abusers Methamphetamine Abuser p < 0.0002

Methamphetamine abusers have significant reductions in dopamine

transporters. BNL - UCLA - SUNY NIDA - ONDCP - DOE

Dopamine Transporters in Methamphetamine Abusers

Motor Task 2.0 1.8 Loss of dopamine transporters

1.6 in the meth abusers may result 1.4 in slowing of motor reactions.

1.2

1.07 8 9 10 11 12 13 Time Gait

(seconds) Bmax/Kd Bmax/Kd 2.0 Dopamine Transporter Dopamine Memory Task 1.8 1.6 Loss of dopamine transporters 1.4 in the meth abusers may result 1.2 in memory impairment. 1.0 16 14 12 10 8 6 4 Delayed Recall (words remembered) BNL/UCLA/SUNY NIDA, ONDCP, DOE

Dopamine D2 Receptors in Addiction

Control Experimental groups groups Cocaine

Meth

Alcohol

Food

Challenge: Normal Drug Use Addiction Treatment

Three Major Relapse Pathways

I. Cross Addicting Drugs II. People/Place/Things III. B.H.A.L.T.

Cross Addicting Drugs

a. Chemical of choice b. Related drugs c. Tobacco d. Life long relapse pathway

People/Place/Things

a. History of discovery b. Three month limit for relapse

B.H.A.L.T.

a. Boredom b. Hunger c. Anger/emotions d. Loneliness e. Tiredness

Relapse Prevention Medications

I. Antabuse II. Campral III. ReVia IV. Vivitrol V. Off label

Antabuse

a. Mechanism of action b. Dosing c. Side Effects d. Efficacy

Campral

a. Mechanism of action b. Dosing c. Side Effects d. Efficacy

ReVia

a. Mechanism of action b. Dosing c. Side Effects d. Efficacy

Vivitrol

a. Mechanism of action b. Dosing c. Side Effects d. Efficacy

Off label

Phase 3 Clinical Trials On A Number of Promising Drugs

Cocaine Methamphetamine Opiates

Cabergoline Bupropion Lofexidine Disulfiram (Antabuse) Reserpine Selegiline

Methamphetamine Addiction Pharmacotherapies Opiate Medication Development Projects inin ClinicalClinical TrialsTrials Phase I Phase II Phase I Phase II Phase III Bupropion Amlodipine Bupropion Cycloserine Bupropion Buprenorphine Disulfiram Baclofen Depot Naltrexone Buspirone Buprenorphine/Naloxone Lobeline Desipramine Enadoline Clonidine Lofexidine Reserpine Fluoxetine Lamotrigine Lofexidine Selegiline Flupenthixol Gabapentin Tramadol Memantine IsradipineIsradipine Methylphenidate Olanzapine Midazolam/N20/N20 Ondansetron Naloxone Pemoline Naltrexone Selegiline Nefazedone Venlafaxine

Cocaine Medication Development Projects

Phase I Phase II Screen Phase II Phase III Amantadine Disulfiram Butorphanol BP 4897 Amlodipine Selegiline TS DAS 431 Cocaine Vaccine Baclofen Selegiline TS Dextromethorphan Bupropion GBR 12909 Butorphanol Metyrapone IsradipineIsradipine Cabergoline Captopril Modafinil Lamotrigine Captopril Memantine Clopidogrel NS 2359 Memantine Disulfiram Tolcapone Ondansetron Gabapentin Sibutramine Memantine Methylphenidate Naltrexone Oxazepam Pemoline Propranolol Reserpine Risperidone SertralineSertraline Taurine Tiagabine Venlafaxine

Dual Diagnosis

1. Prevalence 2. Testing 3. Treatment

Co-Occurring Disorders

Substance Use Mood, Anxiety, ADD Disorder Psychotic

37% of alcohol dependent  another disorder 53% of drug dependent  another disorder

Etiology

Mental Illness Substance Use

–  Symptoms

–  Social skills

–  Medication side effects

Etiology

Substance Use Mental Illness

– Dependence ↑ psychosis, depression, anxiety

– Withdrawal ↑ depression and anxiety

– ? Shared genetics

Anxiety

• Generalized – Pervasive • Panic – Sudden onset and resolution • Social (9% same as general population) – Associated with social situations • PTSD – Hypervigilence resulting from trauma • OCD – Germs, organizing, checking and re-checking

Panic Social PTSD Generalized OCD

Normal Emotional States

Withdrawal from alcohol, benzodiazepines, opiates, and other sedatives mimics anxious state

Treatment – Anxiety • Behavioral – Therapy as good as medications in most research trials – Hypnosis, Biofeedback, Exercise – The Anxiety Cure – Author Dupont • Medications – SSRIs (Prozac, Paxil, Lexapro, Celexa, Zoloft) – SNRIs (Cymbalta, Effexor, Pristiq) – Buspar – Short- term: Inderal, Vistaril, Neurontin – Trazodone

Mood • Depression – Major Depression – Dysthymia

• Mania – Mania – Hypomania

• Bipolar – I – Manic Episode(s) with or without Depressive Episode(s) – II – Depressive Episodes(s) with Hypomania – Cyclothymia – Hypomania and dysthymic episodes

Mania

hypomania

Normal Emotional States

dysthymia

Major Depression

Withdrawal can mimic mania or depression

Treatment - Mood

• Medications – SSRIs, SNRIs – Wellbutrin (Bupropion) – Mood Stabilizers/Augmenters – Lithium, Depakote, Risperidone, Seroquel, Topamax, Lamictal, Trileptal, Abilify, Geodon, Zyprexa

• Behavioral – Therapy = medications for depression – Exercise, diet, sunlight useful

ADD/ADHD

• 25 fold h in Adderall use last

decade

• USA = 80 % of Ritalin used

worldwide

• No study shown long term use

stimulants in adults is good

Symptoms

- Not listening Just gotta be me! Are you talking to me? Gotta Dance! - Fails to finish tasks I’m molting…….. - Difficulty organizing - Loses things - Easily distracted

Other Causes

• Anxiety • Mania • Withdrawal • Learning Disorders

Treating for ADD first can lead to worsening of above

Treatment - ADD

• Therapy and treatment of any underlying learning disability • Exercise • Atypical stimulants – Strattera (amoxetine) • Guanfacine (Tenex, Intuniv) • SNRIs – Effexor, Prestiq • Wellbutrin (Bupropion)

Personality Disorders

• Disorders?

• Phases?

• Artifacts of Addiction?

“so you are anti-social, histrionic, borderline, and narcissistic but otherwise well.”

PERSONALITY DISORDERS • Totality of Emotional + Behavioral Traits • Onset Teens • Enduring, Inflexible, Consistent, Maladaptive

Causes Significant Impairment and/or Distress

Personality Characteristics

Cluster A – Eccentric or Odd Paranoid Suspicious, Jealous, but not Psychotic or Unlawful Schizoid Unemotional, Cold, Indifferent Schizotypal Odd /Magical, not Paranoid

Cluster B – Dramatic, Emotional, or Erratic ASPD Aggressive, Unlawful, Impulsive Borderline Unstable, Chaotic, Impulsive Histrionic Dramatic, Seductive but not Unlawful Narcissistic Self-Centered, Entitled, Lacks Empathy, but not Unlawful

Personality Characteristics

Cluster C – Anxious or Fearful Avoidant Needs people but Fears Relationships

Dependent Needs Relationships, Indecisive, Fears Abandonment

Obsessive- Rigid, Perfectionist + Inefficient Compulsive

Passive- Negative Attitudes with Passive Aggressive Resistance to Demands

Summary

• Very common to have both a substance use disorder and another disorder • Even more common to feel like you have one when using or withdrawing • The six month challenge • The twelve month reward

Spiritual Component of Recovery

Dr. Daniel Boone La Hacienda Treatment Center 800-749-6160 [email protected]