Methamphetamine: What can Brain Imaging Tell Us? Thomas E. Freese, Ph.

D Director Pacific Southwest

Addiction Technology Transfer Center Asst. Research Psychologist Semel Institute for Neuroscience and
Human Behavior David Geffen School of Medicine University of California at Los Angeles www.psattc.org
www.uclaisap.org tefreese@ix.netcom.com Supported by: Supported by: Supported by: National
Institute on Drug Abuse (NIDA) National Institute on Drug Abuse (NIDA) Pacific Southwest Technology
Transfer Center (SAMHSA) Pacific Southwest Technology Transfer Center (SAMHSA) International
Network of Treatment and Rehabilitation Resource Centres (UNODC) International Network of
Treatment and Rehabilitation Resource Centres (UNODC) May 24, 2006 Orlanndo, Florida

2 Methamphetamine Methamphetamine is a powerful central nervous system stimulant that strongly

activates multiple systems in the brain. Methamphetamine is closely related chemically to
amphetamine, but the central nervous system effects of methamphetamine are greater.
Methamphetamine is a powerful central nervous system stimulant that strongly activates multiple
systems in the brain. Methamphetamine is closely related chemically to amphetamine, but the central
nervous system effects of methamphetamine are greater.

3 Forms of Methamphetamine Methamphetamine Powder Description: Beige/yellowy/off-white powder

Base / Paste Methamphetamine Description: ‘Oily’, ‘gunky’, ‘gluggy’ gel, moist, waxy Crystalline
Methamphetamine IDU Description: White/clear crystals/rocks; ‘crushed glass’ / ‘rock salt’

4 EPHEDRINE OH CC HHH 3 CH 3 N

5 The Methamphetamine Epidemic: Admissions/100,000: 1992-2003 It keeps going up

6 Methamphetamine/Amphetamine Treatment Admissions, by Route of Administration: 1992-2002

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

8 People use drugs for two reasons: 1) To feel good. 2) To feel better People use drugs for two reasons:
1) To feel good. 2) To feel better

9 In other words: A Major Reason People Take a Drug is they Like What It Does to Their Brains In other
words: A Major Reason People Take a Drug is they Like What It Does to Their Brains

10 0 0 50 100 150 200 0 0 60 120 180 Time (min) % of Basal DA Output NAc shell Empty Box Feeding
Source: Di Chiara et al. FOOD Natural Rewards Elevate Dopamine Levels Natural Rewards Elevate
Dopamine Levels

11 Source: Shoblock and Sullivan; Di Chiara and Imperato Effects of Drugs on Dopamine Release 0 0 100
200 300 400 Time After Cocaine % of Basal Release DA DOPAC HVA Accumbens COCAINE 100 150 200
250 01234hr Time After Ethanol % of Basal Release 0.25 0.5 1 2.5 Accumbens 0 Dose (g/kg ip) ETHANOL
0 0 100 150 200 250 0 0 1 1 2 2 3 hr Time After Nicotine % of Basal Release Accumbens Caudate
NICOTINE Time After Methamphetamine % Basal Release METHAMPHETAMINE 0123hr 1500 1000 500 0
Accumbens

12 What Can Imaging Tell Us? In design of new medications – knowledge of affected circuitry can point
to chemical dysfunction that may be helped by medication. In design of new medications – knowledge
of affected circuitry can point to chemical dysfunction that may be helped by medication. In the design
of behavioral treatments it can tell you the types and severity of deficits and dysfunctions in the brain
and the timetable of their recovery (or not). This information can be helpful in guiding the behavioral
targets for treatment and the types and durations of treatment that can best accommodate the brain
recovery In the design of behavioral treatments it can tell you the types and severity of deficits and
dysfunctions in the brain and the timetable of their recovery (or not). This information can be helpful in
guiding the behavioral targets for treatment and the types and durations of treatment that can best
accommodate the brain recovery Brain imaging can show how much viable tissue there is to work with.
And, it can show the affect of treatment. Brain imaging can show how much viable tissue there is to
work with. And, it can show the affect of treatment.

13 Imaging Modalities Regional Function Specific Neurochemistry PETMetabolism Blood Flow

Neurotransmitters & their Receptors SPECT Blood Flow “poor- mans PET” Neurotransmitters & their
Receptors MRI Correlates of Blood Flow 1. Spectroscopy 2. Diffusion Tensor Imaging

14 Brain Function in Methamphetamine Abusers Do METH abusers show abnormalities in brain

metabolites? Do METH abusers show abnormalities in brain metabolites? Do brain metabolite
abnormalities relate to cognitive performance – such as selective attention? Do brain metabolite
abnormalities relate to cognitive performance – such as selective attention? Does the brain recover
following cessation of METH use? Does the brain recover following cessation of METH use?

15 Prolonged Drug Use Changes the Brain In Fundamental and Long-Lasting Ways

16 Source: McCann U.D.. et al.,Journal of Neuroscience, 18, pp. 8417-8422, October 15, 1998. Decreased
dopamine transporter binding in METH users resembles that in Parkinson ’ s Disease Control Meth PD

17 Partial Recovery of Brain Dopamine Transporters in Methamphetamine 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.

22 Meth

26 Their Brains have been Re-Wired by Drug Use Their Brains have been Re-Wired by Drug Use
Because…

27 Some Recent Findings Methamphetamine abusers have deficits in: prefrontal cortex (working
memory) Edythe London et al prefrontal cortex (working memory) Edythe London et al anterior
cingulate gyrus (selective attention) Nordahl, Salo et al, Salo, Nordahl et al, Taylor et al anterior cingulate
gyrus (selective attention) Nordahl, Salo et al, Salo, Nordahl et al, Taylor et al temporal lobe (episodic
memory, depression) London et al temporal lobe (episodic memory, depression) London et al

28 Speculation Cognitive deficits in methamphetamine abusers are likely to reflect damage in anterior
brain regions, such as anterior cingulum, that could contribute to their clinical presentation of
inattention and distractibility. Cognitive deficits in methamphetamine abusers are likely to reflect
damage in anterior brain regions, such as anterior cingulum, that could contribute to their clinical
presentation of inattention and distractibility.

29 Control > MA 4 3 2 0 1

30 MA > Control 5 4 2 0 1 3

31 Cognitive and Memory Effects

32 Differences between Stimulant and Comparison Groups on tests requiring perceptual speed

33 Memory Difference between Stimulant and Comparison Groups

34 Longitudinal Memory Performance test number correct

36 Defining Domains: Executive Systems Functioning a.k.a. frontal lobe functioning. a.k.a. frontal lobe
functioning. Deficits on executive tasks assoc. w/: Deficits on executive tasks assoc. w/: –Poor judgment.
–Lack of insight. –Poor strategy formation. –Impulsivity. –Reduced capacity to determine consequences
of actions.

37 Brain Serotonin Transporter Density and Aggression in Abstinent Methamphetamine Abusers Sekine,
Y, Ouchi, Y, Takei, N, et al. Brain Serotonin Transporter Density and Aggression in Abstinent
Methamphetamine Abusers. Arch Gen Psychiatry. 2006;63:90-100.

38 Objective of Study Investigate the status of brain serotonin neurons and their possible relationship
with clinical characteristics in currently abstinent methamphetamine abusers. Investigate the status of
brain serotonin neurons and their possible relationship with clinical characteristics in currently abstinent
methamphetamine abusers.

39 Results 1. Serotonin transporter density in global brain regions was significantly lower in
methamphetamine abusers Suggests that abuse of methamphetamine leads to a global and severe
reduction in the density of human brain serotonin transportersSuggests that abuse of
methamphetamine leads to a global and severe reduction in the density of human brain serotonin
transporters 2. Values of serotonin transporter density in widely distributed brain regions were found to
negatively correlate with the duration of methamphetamine use. Suggests that the longer
methamphetamine is used, the more severe the decrease in serotonin transporter density.Suggests that
the longer methamphetamine is used, the more severe the decrease in serotonin transporter density.

40 Results (Continued) 3. Magnitude of aggression in methamphetamine abusers increased significantly

with decreasing serotonin transporter densities in some brain regions. Bitofrontal cortex, anterior
cingulate, temporal cortexBitofrontal cortex, anterior cingulate, temporal cortex 4. No correlation
between a representative measure of serotonin transporter density and the duration of
methamphetamine abstinence. Individuals abstinent for > 1 year still had a substantial decrease in
serotonin transporter density. Suggests reductions in the density of the serotonin transporter in the
brain could persist long after methamphetamine use ceases.Suggests reductions in the density of the
serotonin transporter in the brain could persist long after methamphetamine use ceases.

41 Methamphetamine Use, Self-Reported Violent Crime, and Recidivism Among Offenders in California
Who Abuse Substances Cartier J, Farabee D, Prendergast M. Methamphetamine Use, Self- Reported
Violent Crime, and Recidivism Among Offenders in California Who Abuse Substances. Journal of
Interpersonal Violence. 2006;21:435-445.

42 Objective of Study Examine the associations between methamphetamine (MA) use and three
measures of criminal behavior: (a) self-reported violent criminal behavior, (b) return to prison for a
violent offense, and (c) return to prison for any reason. Examine the associations between
methamphetamine (MA) use and three measures of criminal behavior: (a) self-reported violent criminal
behavior, (b) return to prison for a violent offense, and (c) return to prison for any reason.
43 Methods Participants Participants –808 low- to medium-level inmates Clear history of substance
abuse Clear history of substance abuse Within 12 months of release Within 12 months of release Half
the sample entering an in-prison substance abuse (SA) program and the other half from a neighboring
prison that offered no formal SA treatment Half the sample entering an in-prison substance abuse (SA)
program and the other half from a neighboring prison that offered no formal SA treatment Matched by
age, ethnicity, sex offender status, and commitment offense Matched by age, ethnicity, sex offender
status, and commitment offense

44 Methods Continued Baseline and 12-Month Follow-Up InterviewsBaseline and 12-Month Follow-Up
Interviews Modified versions of criminal justice treatment evaluation forms developed by researchers at
Texas Christian University Modified versions of criminal justice treatment evaluation forms developed by
researchers at Texas Christian University Sections on sociodemographic background, family and peer
relations, health and psychological status, criminal involvement, in-depth drug-use history, and an AIDS-
risk assessment Sections on sociodemographic background, family and peer relations, health and
psychological status, criminal involvement, in-depth drug-use history, and an AIDS-risk assessment

45 Results Those who used MA (81.6%) were significantly more likely than those who did not use MA
(53.9%) to have been returned to custody for any reason or to report committing any violent acts in the
30 days prior to follow-up (23.6% vs. 6.8%, respectively) Those who used MA (81.6%) were significantly
more likely than those who did not use MA (53.9%) to have been returned to custody for any reason or
to report committing any violent acts in the 30 days prior to follow-up (23.6% vs. 6.8%, respectively)

46 Results Continued After controlling for drug trade involvement, MA use was still significantly
predictive of self-reported violent crime and general recidivism After controlling for drug trade
involvement, MA use was still significantly predictive of self-reported violent crime and general
recidivism

47 Implications of Results These findings suggest that offenders who use MA may differ significantly
from their peers who do not use MA and may require more intensive treatment interventions and
parole supervision than other types of offenders who use drugsThese findings suggest that offenders
who use MA may differ significantly from their peers who do not use MA and may require more
intensive treatment interventions and parole supervision than other types of offenders who use drugs

48 Neural Activation Patterns of Methamphetamine-Dependent Subjects During Decision Making Predict

Relapse Paulus M, Tapert S, Schuckit M. Neural Activation Patterns of Methamphetamine-Dependent
Subjects During Decision Making Predict Relapse. Arch Gen Psychiatry. 2005;62:761-768.

49 Objective of Study To determine whether functional magnetic resonance imaging (fMRI) during a
decision-making task can be used to predict relapse in treatment- seeking methamphetamine-
dependent individuals To determine whether functional magnetic resonance imaging (fMRI) during a
decision-making task can be used to predict relapse in treatment- seeking methamphetamine-
dependent individuals

50 Methods Participants Participants –46 treatment-seeking males Met criteria for current dependence
on methamphetamine (MA) Met criteria for current dependence on methamphetamine (MA) Not
dependent on any other drug or on alcohol Not dependent on any other drug or on alcohol Voluntarily
entered and completed a 28- day inpatient program Voluntarily entered and completed a 28- day
inpatient program At the time of scanning, abstinent from MA At the time of scanning, abstinent from
MA

51 Methods Continued Interview-based symptomatic assessmentInterview-based symptomatic

assessment fMRI tasksfMRI tasks 2-choice prediction task 2-choice prediction task Response task
Response task Outcome measureOutcome measure Blood oxygen level-dependent fMRI activation
during tasks Blood oxygen level-dependent fMRI activation during tasks

52 Methods Continued Follow-Up Follow-Up –Contacted 1 year after imaging session –Sobriety assessed
using a questionnaire –Relapse defined as any use of MA during any time after discharge

53 Results 18 of 40 subjects relapsed 18 of 40 subjects relapsed Bilateral prefrontal cortex, striatum,

posterior parietal cortex, and anterior insula were more active during the prediction task than the
response task Bilateral prefrontal cortex, striatum, posterior parietal cortex, and anterior insula were
more active during the prediction task than the response task

54 Results Continued 9 areas within these regions differentiated relapsing and nonrelapsing participants
9 areas within these regions differentiated relapsing and nonrelapsing participants –Areas included
prefrontal, parietal, and insular cortex –Nonrelapsing individuals showed more activation in these areas

55 Results Continued –Right insula, right posterior cingulate, and right middle temporal gyrus response
best differentiated between relapsing and nonrelapsing participants Cross-validation analysis was able
to correctly predict 19 of 22 who did not relapse and 17 of 18 who relapsed Cross-validation analysis
was able to correctly predict 19 of 22 who did not relapse and 17 of 18 who relapsed –Right middle
frontal gyrus, right middle temporal gyrus, and right posterior cingulate cortex activation best predicted
time to relapse

56 Implications of Results Neural activation differences are part of a system involved with the processing
of decision making. Attenuated activation may represent:Neural activation differences are part of a
system involved with the processing of decision making. Attenuated activation may represent: Defective
assessment abilities and subsequent reliance on habitual behaviors Defective assessment abilities and
subsequent reliance on habitual behaviors Diminished ability to differentiate choices that lead to good
vs. poor outcomes Diminished ability to differentiate choices that lead to good vs. poor outcomes fMRI
may prove to be a useful clinical tool to assess relapse susceptibilityfMRI may prove to be a useful
clinical tool to assess relapse susceptibility

57 Methamphetamine Abuse, HIV Infection Causes Changes in Brain Structure Jernigan,T, et al American
Jnl of Psychiatry Aug 2005 Methamphetamine abuse and HIV infection cause significant alterations in
the size of certain brain structures, and in both cases the changes may be associated with impaired
cognitive functions, such as difficulties in learning new information, solving problems, maintaining
attention and quickly processing information. Methamphetamine abuse and HIV infection cause
significant alterations in the size of certain brain structures, and in both cases the changes may be
associated with impaired cognitive functions, such as difficulties in learning new information, solving
problems, maintaining attention and quickly processing information. Co-occurring methamphetamine
abuse and HIV infection appears to result in greater impairment than each condition alone Co-occurring
methamphetamine abuse and HIV infection appears to result in greater impairment than each condition
alone
58 Methamphetamine Abuse, HIV Infection Causes Changes in Brain Structure Jernigan,T, et al American
Jnl of Psychiatry Aug 2005 Brain scans to analyze structural volume changes in 103 adults divided among
four populations: methamphetamine abusers who were HIV-positive; methamphetamine abusers who
were HIV- negative; nonabusers who were HIV-positive; and nonabusers who were HIV-negative. Brain
scans to analyze structural volume changes in 103 adults divided among four populations:
methamphetamine abusers who were HIV-positive; methamphetamine abusers who were HIV-
negative; nonabusers who were HIV-positive; and nonabusers who were HIV-negative. They also
assessed the ability to think and reason using a detailed battery of tests that examined speed of
information processing, attention/working memory, learning and delayed recall, abstraction/executive
functioning, verbal fluency, and motor functioning. They also assessed the ability to think and reason
using a detailed battery of tests that examined speed of information processing, attention/working
memory, learning and delayed recall, abstraction/executive functioning, verbal fluency, and motor
functioning.

59 Methamphetamine Abuse, HIV Infection Causes Changes in Brain Structure Jernigan,T, et al American
Jnl of Psychiatry Aug 2005 Methamphetamine abuse is associated with changes in the the brain’s
parietal cortex (which helps people to understand and pay attention to what’s going on around them)
and basal ganglia (linked to motor function and motivation). Methamphetamine abuse is associated with
changes in the the brain’s parietal cortex (which helps people to understand and pay attention to what’s
going on around them) and basal ganglia (linked to motor function and motivation). The degree of
change in the parietal cortex was associated with worse cognitive function The degree of change in the
parietal cortex was associated with worse cognitive function HIV infection is associated with prominent
volume losses in the cerebral cortex (involved in higher thought, reasoning, and memory), basal ganglia,
and hippocampus (involved in memory and learning) HIV infection is associated with prominent volume
losses in the cerebral cortex (involved in higher thought, reasoning, and memory), basal ganglia, and
hippocampus (involved in memory and learning)

60 Methamphetamine Abuse, HIV Infection Causes Changes in Brain Structure Jernigan,T, et al American
Jnl of Psychiatry Aug 2005 “In HIV-infected people, the cognitive impairments are associated with
decreased employment and vocational abilities, difficulties with medication management, impaired
driving performance, and problems with general activities of daily living, such as managing money,” “In
HIV-infected people, the cognitive impairments are associated with decreased employment and
vocational abilities, difficulties with medication management, impaired driving performance, and
problems with general activities of daily living, such as managing money,” “The impact of
methamphetamine could potentially affect treatment and relapse prevention efforts, as well as things
like money management and driving performance.” “The impact of methamphetamine could potentially
affect treatment and relapse prevention efforts, as well as things like money management and driving
performance.”

61 Methamphetamine Abuse, HIV Infection Causes Changes in Brain Structure Jernigan,T, et al American
Jnl of Psychiatry Aug 2005 Younger methamphetamine abusers showed larger effects in some brain
regions. Younger methamphetamine abusers showed larger effects in some brain regions. Among HIV-
infected individuals, the researchers noted a direct association between the severity of the infection and
greater loss of brain matter. Among HIV-infected individuals, the researchers noted a direct association
between the severity of the infection and greater loss of brain matter. In methamphetamine abusers
who are also HIV-positive, decreased volumes are correlated with increased cognitive impairment in one
brain region, the hippocampus. In methamphetamine abusers who are also HIV-positive, decreased
volumes are correlated with increased cognitive impairment in one brain region, the hippocampus.

66 For more information, contact: Thomas E. Freese, Ph.D. 310-445-0874 x304 tefreese@ix.netcom.com

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