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 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

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.

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’

EPHEDRINE OH CC HHH 3 CH 3 N

The Methamphetamine Epidemic: Admissions/100,000: It keeps going up

Methamphetamine/Amphetamine Treatment Admissions, by Route of Administration: Source: 2002 SAMHSA Treatment Episode Data Set (TEDS).

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

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

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

Source: Shoblock and Sullivan; Di Chiara and Imperato Effects of Drugs on Dopamine Release Time After Cocaine % of Basal Release DA DOPAC HVA Accumbens COCAINE hr Time After Ethanol % of Basal Release Accumbens 0 Dose (g/kg ip) ETHANOL hr Time After Nicotine % of Basal Release Accumbens Caudate NICOTINE Time After Methamphetamine % Basal Release METHAMPHETAMINE 0123hr Accumbens

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.

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

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?

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

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

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, , 2001.

Meth

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

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

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.

Control > MA

MA > Control

Cognitive and Memory Effects

Differences between Stimulant and Comparison Groups on tests requiring perceptual speed

Memory Difference between Stimulant and Comparison Groups

Longitudinal Memory Performance test number correct

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.

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:

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.

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.

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.

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:

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.

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

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

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)

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

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

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:

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

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

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

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

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

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

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

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

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

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.

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)

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.”

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.

For more information, contact: Thomas E. Freese, Ph.D x304