Methamphetamine and the Methamphetamine and the Brain: New Knowledge; New Brain: New Knowledge; New

TreatmentsTreatmentsRichard A. Rawson, Ph.DRichard A. Rawson, Ph.D

Adjunct Associate ProfessorAdjunct Associate ProfessorSemel Institute for Neuroscience and Human BehaviorSemel Institute for Neuroscience and Human Behavior

David Geffen School of MedicineDavid Geffen School of MedicineUniversity of California at Los AngelesUniversity of California at Los Angeles

www.uclaisap.orgwww.uclaisap.orgrrawson@mednet.ucla.edurrawson@mednet.ucla.edu

Supported by:Supported by: National Institute on Drug Abuse (NIDA)National Institute on Drug Abuse (NIDA)

Pacific Southwest Technology Transfer CenterPacific Southwest Technology Transfer Center (SAMHSA) (SAMHSA)International Network of Treatment and Rehabilitation Resource Centres (UNODC)International Network of Treatment and Rehabilitation Resource Centres (UNODC)

MethamphetamineMethamphetamine

The DrugThe Drug

Forms of MethamphetamineForms of Methamphetamine

Methamphetamine Powder

IDU Description: Beige/yellowy/off-white powder

Base / Paste Methamphetamine

IDU Description: ‘Oily’, ‘gunky’, ‘gluggy’ gel, moist, waxy

Crystalline Methamphetamine

IDU Description: White/clear crystals/rocks; ‘crushed glass’ / ‘rock salt’

EPHEDRINE

OH

CC

HHH

3CH 3CH

N

M ETH AM PH ETAM IN E

H

CC

HHH

3CH 3CH

N

MethamphetamineMethamphetamine

The US EpidemicThe US Epidemic

According to surveys and estimates by WHO According to surveys and estimates by WHO and UNODC, methamphetamine is the most and UNODC, methamphetamine is the most widely used illicit drug in the world except for widely used illicit drug in the world except for cannabis.cannabis.

World wide it is estimated there are over 26 World wide it is estimated there are over 26 million regular users of million regular users of amphetamine/methamphetamine, as compared amphetamine/methamphetamine, as compared to approximately 16 million heroin users and 14 to approximately 16 million heroin users and 14 million cocaine usersmillion cocaine users

Scope of the Methamphetamine Scope of the Methamphetamine Problem WorldwideProblem Worldwide

The Methamphetamine Epidemic:The Methamphetamine Epidemic:Admissions/100,000: 1992-2003Admissions/100,000: 1992-2003

0

50

100

150

200

250

300

350

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

California

Hawaii

I owa

Oregon

Washington

It keeps going up

Figure 1. Methamphetamine/Amphetamine Treatment Admission Rate per 100,000 Population Aged 12 or Older:

1992-2002

Source: 2002 SAMHSA Treatment Episode Data Set (TEDS).

Figure 2. Methamphetamine/Amphetamine Treatment Admissions, by Route of Administration: 1992-2002

Source: 2002 SAMHSA Treatment Episode Data Set (TEDS).

The Eastward Spread of The Eastward Spread of MethamphetamineMethamphetamine

Primary Amphetamine/Methamphetamine Primary Amphetamine/Methamphetamine TEDS Admission Rates: 1992TEDS Admission Rates: 1992

(per 100,000 aged 12 and over)(per 100,000 aged 12 and over)

35 - 5812 - 35

< 12No data

> 58

< 12

Primary Amphetamine/Methamphetamine Primary Amphetamine/Methamphetamine TEDS Admission Rates: 1997TEDS Admission Rates: 1997

(per 100,000 aged 12 and over)(per 100,000 aged 12 and over)

35 - 5812 - 35

< 12No

data

> 58

Primary Amphetamine/Methamphetamine Primary Amphetamine/Methamphetamine TEDS Admission Rates: 2003TEDS Admission Rates: 2003

(per 100,000 aged 12 and over)(per 100,000 aged 12 and over)

127+< 5

5 - 5960-126

Incomplete Data

Methamphetamine: A Growing Menace Methamphetamine: A Growing Menace in Rural Americain Rural America

In 1998, rural areas In 1998, rural areas nationwide reported 949 nationwide reported 949 methamphetamine labs. methamphetamine labs.

Last year, 9,385 were Last year, 9,385 were reported. reported.

This year, 4,589 rural labs This year, 4,589 rural labs had been reported as of had been reported as of July 26.July 26.

Source: El Paso Intelligence Center (EPIC), Source: El Paso Intelligence Center (EPIC), U.S. DEAU.S. DEA

MethamphetamineMethamphetamine

Medical/Psychiatric Effects Medical/Psychiatric Effects and Consequencesand Consequences

Cardiovascular problemsCardiovascular problems

↑ ↑ Heart rateHeart ratePalpitations Palpitations Arrhythmia Arrhythmia ↑ ↑ Blood pressureBlood pressure Chest Pain Chest Pain – Acute coronary syndrome Acute coronary syndrome

Valve thickening Valve thickening

Neurological problemsNeurological problems

Seizures Seizures

Stroke Stroke

Cerebral Cerebral hemorrhage hemorrhage

Cerebral vasculitis Cerebral vasculitis

MydriasisMydriasis

Respiratory problemsRespiratory problems

Dyspnea Dyspnea

Pulmonary Pulmonary

hypertension hypertension

Pleuritic chest pain Pleuritic chest pain

Other problemsOther problems

Eye ulcers Eye ulcers

Over-heatingOver-heating

Rhabdomyolysis Rhabdomyolysis

Obstetric complications Obstetric complications

Anorexia / weight loss Anorexia / weight loss

Tooth wear, cavitiesTooth wear, cavities

““Speed bumps”Speed bumps”

TraumaTrauma

Interpersonal Interpersonal traumatrauma– AssaultAssault

– GunshotGunshot

– KnifeKnife

Motor VehiclesMotor Vehicles

Suicide attemptsSuicide attempts

MethamphetamineMethamphetamine

The BrainThe Brain

A Major Reason People Take a Drug is they Like

What It Does to Their Brains

A Major Reason People Take a Drug is they Like

What It Does to Their Brains

00

5050

100100

150150

200200

00 6060 120120 180180

Time (min)Time (min)

% o

f B

asal

DA

Ou

tpu

t%

of

Bas

al D

A O

utp

ut

NAc shellNAc shell

EmptyEmpty

BoxBox FeedingFeeding

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

FOODFOOD

100100

150150

200200

DA

Co

nce

ntr

ati

on

(%

Bas

elin

e)D

A C

on

cen

tra

tio

n (

% B

asel

ine)

MountsMountsIntromissionsIntromissionsEjaculationsEjaculations

1515

00

55

1010

Co

pu

latio

n F

req

ue

nc

yC

op

ula

tion

Fre

qu

en

cy

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

SEXSEX

Natural Rewards Elevate Dopamine Natural Rewards Elevate Dopamine LevelsLevels

Natural Rewards Elevate Dopamine Natural Rewards Elevate Dopamine LevelsLevels

00

100100

200200

300300

400400

Time After CocaineTime After Cocaine

% o

f B

as

al

Re

lea

se

% o

f B

as

al

Re

lea

se

DADADOPACDOPACHVAHVA

AccumbensAccumbensCOCAINECOCAINE

00

100100

150150

200200

250250

00 11 22 3 hr3 hr

Time After NicotineTime After Nicotine

% o

f B

as

al

Re

lea

se

% o

f B

as

al

Re

lea

se

AccumbensAccumbensCaudateCaudate

NICOTINENICOTINE

Source: Shoblock and Sullivan; Di Chiara and Imperato

Effects of Drugs on Dopamine ReleaseEffects of Drugs on Dopamine Release

100

150

200

250

0 1 2 3 4hrTime After Ethanol

% o

f B

as

al

Re

lea

se

0.250.512.5

Accumbens

0

Dose (g/kg ip)

ETHANOLETHANOL

Time After Methamphetamine

% B

as

al

Re

lea

se

METHAMPHETAMINE

0 1 2 3hr

1500

1000

500

0

Accumbens

Prolonged Drug Use ChangesProlonged Drug Use Changesthe Brain In Fundamentalthe Brain In Fundamentaland Long-Lasting Waysand Long-Lasting Ways

Source: McCann U.D.. et al.,Journal of Neuroscience, 18, pp. 8417-8422, October 15, 1998.

Decreased dopamine transporter binding in METH Decreased dopamine transporter binding in METH users resembles that inusers resembles that in

Parkinson’s Disease patients Parkinson’s Disease patients

Control Methamphetamine PD

Partial Recovery of Brain Dopamine Transporters in Methamphetamine

(METH)Abuser After Protracted Abstinence

Normal Control METH Abuser(1 month detox)

METH Abuser(24 months detox)

0

3

ml/gm

Source: Volkow, ND et al., Journal of Neuroscience 21, 9414-9418, 2001.

Prolonged Drug Use ChangesProlonged Drug Use Changesthe Brain In Fundamentalthe Brain In Fundamentaland Long-Lasting Waysand Long-Lasting Ways

My sexual My sexual drivedrive is increased by the use of … is increased by the use of …

18.1 20.5

43.9

70.655.3

11.1

85.3

55.6

0102030405060708090

100

Per

cent

Res

pond

ing

"Yes

"

opiates alcohol cocaine meth

Primary Drug of Abuse

malefemale

(Rawson et al., 2002)

My sexual activity is increased by the use of …My sexual activity is increased by the use of …

16.0 18.224.4

38.244.7

11.1

73.5 66.7

0102030405060708090

100

Per

cent

Res

pond

ing

"Yes

"

opiates alcohol cocaine meth

Primary Drug of Abuse

malefemale

(Rawson et al., 2002)

My sexual My sexual performanceperformance is improved by the use of is improved by the use of ……

19.115.9

24.432.4

18.411.1

58.8 61.1

0102030405060708090

100

Per

cent

Res

pond

ing

"Yes

"

opiates alcohol cocaine meth

Primary Drug of Abuse

malefemale

(Rawson et al., 2002)

MethamphetamineMethamphetamine

TreatmentTreatment

MA Treatment IssuesMA Treatment Issues

Acute MA OverdoseAcute MA Overdose

Acute MA PsychosisAcute MA Psychosis

MA “Withdrawal”MA “Withdrawal”

Initiating MA AbstinenceInitiating MA Abstinence

MA Relapse PreventionMA Relapse Prevention

Protracted Cognitive Impairment Protracted Cognitive Impairment and Symptoms of Paranoiaand Symptoms of Paranoia

MA “Withdrawal”MA “Withdrawal”

- Depression- Depression - Paranoia- Paranoia

- Fatigue- Fatigue - Cognitive - Cognitive ImpairmentImpairment

- Anxiety- Anxiety - Agitation- Agitation

- Anergia- Anergia - Confusion- Confusion

Duration: 2 Days - 2 WeeksDuration: 2 Days - 2 Weeks

MedicationsMedications

Currently, there are no medications that can Currently, there are no medications that can quickly and safely reverse life threatening quickly and safely reverse life threatening MA overdose.MA overdose.

There are no medications that can reliably There are no medications that can reliably reduce paranoia and psychotic symptoms, reduce paranoia and psychotic symptoms, that contribute to episodes of dangerous and that contribute to episodes of dangerous and violent behavior associated with MA use.violent behavior associated with MA use.

Bupropion: An efficacious Bupropion: An efficacious pharmacotherapy? pharmacotherapy?

Newton et al 2005 Bupropion reduces Newton et al 2005 Bupropion reduces craving and reinforcing effects of methcraving and reinforcing effects of meth

Elkashef (recently completed) Bupropion Elkashef (recently completed) Bupropion reduces meth use in an outpatient trial, reduces meth use in an outpatient trial, with particularly strong effect with less with particularly strong effect with less severe users. severe users.

Special treatment consideration should be made for Special treatment consideration should be made for the following groups of individuals:the following groups of individuals:

Female MA users (higher rates of depression; very high rates of Female MA users (higher rates of depression; very high rates of previous and present sexual and physical abuse; responsibilities for previous and present sexual and physical abuse; responsibilities for children).children).

Injection MA users (very high rates of psychiatric symptoms; severe Injection MA users (very high rates of psychiatric symptoms; severe withdrawal syndromes; high rates of hepatitis).withdrawal syndromes; high rates of hepatitis).

MA users who take MA daily or in very high doses.MA users who take MA daily or in very high doses.

Homeless, chronically mentally ill and/or individuals with high levels of Homeless, chronically mentally ill and/or individuals with high levels of psychiatric symptoms at admission.psychiatric symptoms at admission.

Individuals under the age of 21.Individuals under the age of 21.

Gay men (at very high risk for HIV and hepatitis).Gay men (at very high risk for HIV and hepatitis).

Treatments for Stimulant-use Disorders with Treatments for Stimulant-use Disorders with Empirical SupportEmpirical Support

Motivational InterviewingMotivational Interviewing

Cognitive-Behavioral Therapy (CBT)Cognitive-Behavioral Therapy (CBT)

Community Reinforcement Approach Community Reinforcement Approach

Contingency ManagementContingency Management

12 Step Facilitation12 Step Facilitation

Matrix ModelMatrix Model

Brief InterventionsBrief Interventions

Methamphetamine Treatment: Controlled Methamphetamine Treatment: Controlled Clinical TrialsClinical Trials

Contingency ManagementContingency Management

Matrix ModelMatrix Model

Contingency ManagementContingency Management

A technique employing the systematic A technique employing the systematic delivery of positive reinforcement for delivery of positive reinforcement for desired behaviors. In the treatment of desired behaviors. In the treatment of methamphetamine dependence, vouchers methamphetamine dependence, vouchers or prizes can be “earned” for submission or prizes can be “earned” for submission of methamphetamine-free urine samples.of methamphetamine-free urine samples.

Mean number of abstinences

0

5

10

15

20

25

CM Control

Mean weeks of consecutive abstinence

0

1

2

3

4

5

6

CM Control

Methamphetamine Outcomes from CTN Methamphetamine Outcomes from CTN 006006

0

2

4

6

8

10

12

14

16

LDA # Negative Urine

Nu

mb

er

of

sa

mp

les

CM (n=55)

Standard care (n=69)

Baseline DemographicsBaseline Demographics

Participants Served (n)Participants Served (n) 10161016

Age (mean)Age (mean) 32.8 years32.8 years

Education (mean)Education (mean) 12.2 years12.2 years

Methamphetamine Use (mean)Methamphetamine Use (mean) 7.5 years7.5 years

Marijuana Use (mean)Marijuana Use (mean) 7.2 years7.2 years

Alcohol Use (mean)Alcohol Use (mean) 7.6 years7.6 years

Gender Distribution of Gender Distribution of ParticipantsParticipants

45

55

0

10

20

30

40

50

60

female male

Gender

Per

cent

Days of Methamphetamine Use in Past Days of Methamphetamine Use in Past 30 (ASI)30 (ASI)

4.4

11.5

0

2

4

6

8

10

12

BL Tx end

Mea

n D

ays U

se

Possible is 0-30; tpaired=20.90; p-value<0.000 (highly sig.)

Mean Number of Weeks in Treatment

02468

1012

SITE

mea

n nu

mbe

r of

vis

its MatrixTAU

Mean Number of UA’s that were MA-free Mean Number of UA’s that were MA-free during treatmentduring treatment

0

2

4

6

8

10

SITE

mea

n nu

mbe

r of

MA

-fre

e U

A's Matrix

TAU

Urinalysis Results Urinalysis Results

Results of Ua Tests at Discharge, 6 Results of Ua Tests at Discharge, 6 months and 12 Months post admission **months and 12 Months post admission **

Matrix GroupMatrix Group TAU GroupTAU Group

D/C: 66% MA-freeD/C: 66% MA-free 65% MA-free 65% MA-free

6 Ms: 69% MA-free6 Ms: 69% MA-free 67% MA-free 67% MA-free

12 Ms: 59% MA-free12 Ms: 59% MA-free 55% MA-free 55% MA-free

**Over 80% follow up rate in both groups at all points**Over 80% follow up rate in both groups at all points

Treatment of MA-Use DisordersTreatment of MA-Use Disorders

No medications currently are available with No medications currently are available with evidence of efficacyevidence of efficacy

Two approaches, Contingency Management and Two approaches, Contingency Management and Matrix Model have data to support efficacyMatrix Model have data to support efficacy

MA users appear to respond to other MA users appear to respond to other psychosocial treatments in a manner psychosocial treatments in a manner comparable to other categories of drug users.comparable to other categories of drug users.

MA users are responsive to treatmentMA users are responsive to treatment