Methamphetamine: What can Brain Imaging Tell Us?

1. Methamphetamine: What can Brain Imaging Tell Us? Richard A. Rawson, Ph.D Adjunct Associate Professor Semel Institute for Neuroscience and Human Behavior David Geffen School of Medicine University of California at Los Angeles www.uclaisap.org rrawson@mednet.ucla.edu Supported by: Supported by: National Institute on Drug Abuse (NIDA) Pacific Southwest Technology Transfer Center (SAMHSA) International Network of Treatment and Rehabilitation Resource Centres (UNODC)

2. 33-year-old man, high on methamphetamine, attempts suicide with a nail gun • Man initially entered the hospital complaining of a headache. • Doctors did not see the nails during the initial examination, but x-rays revealed 12 nails, 1 ½ to 2 inches long, embedded in his head. Source: Skidmore, S. (2006, April 21) Oregon Man Survives 12 Nails to the Head. TheAssociated Press.

3. The man at first claimed it was an accident, but he later admitted that it was a suicide attempt. • The nails were removed, and the man survived without any serious permanent damage. • He was eventually transferred to psychiatric care; he stayed for almost one month under court order but then left against doctors’ orders MSNBC-TV

4. 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.

5. Forms 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’

6. EPHEDRINE H H H C C N CH CH OH 3 3

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

8. Figure 2. Methamphetamine/Amphetamine Treatment Admissions, by Route of Administration: 1992-2002 Source: 2002 SAMHSA Treatment Episode Data Set (TEDS).

9. 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 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.

10. Imaging Modalities

11. Brain Function in Methamphetamine Abusers • Do METH abusers show abnormalities in brain metabolites? • Do brain metabolite abnormalities relate to cognitive performance – such as selective attention? • Does the brain recover following cessation of METH use?

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

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

14. Partial Recovery of Brain Dopamine Transporters in Methamphetamine (METH) Abuser After Protracted Abstinence 3 0 ml/gm METH Abuser (1 month detox) Normal Control METH Abuser (24 months detox) Source: Volkow, ND et al., Journal of Neuroscience 21, 9414-9418, 2001.

15. Some Recent Findings Methamphetamine abusers have deficits in: • prefrontal cortex (working memory) Edythe London 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

16. 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.

17. Control > MA 4 3 2 1 0

18. 5 4 3 2 1 0 MA > Control

19. Methamphetamine Cognitive and Memory Effects

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

22. Anhydrous Ammonia Tank Tips Officers to Possible Meth Lab 5/4/04 Omaha, Neb. – A large anhydrous ammonia tank helped Sarpy County Sheriff’s deputies bust a suspected methamphetamine lab Tuesday. SOURCE: TheOmahaChannel.com

23. 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.

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

25. Results • 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 transporters • 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.

26. Results (Continued) • Magnitude of aggression in methamphetamine abusers increased significantly with decreasing serotonin transporter densities in some brain regions. • Bitofrontal cortex, anterior cingulate, temporal cortex • 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.

27. 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.

28. 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.

29. Methods • Participants • 808 low- to medium-level inmates • Clear history of substance abuse • 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 • Matched by age, ethnicity, sex offender status, and commitment offense

30. Methods Continued • Baseline and 12-Month Follow-Up Interviews • 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

31. 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)

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

33. 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 drugs

34. 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.

35. 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

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

37. Methods Continued • Interview-based symptomatic assessment • fMRI tasks • 2-choice prediction task • Response task • Outcome measure • Blood oxygen level-dependent fMRI activation during tasks

38. Methods Continued • 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

39. Results • 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

40. Results Continued • 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

41. 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 • Right middle frontal gyrus, right middle temporal gyrus, and right posterior cingulate cortex activation best predicted time to relapse

42. Implications of Results • 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 • Diminished ability to differentiate choices that lead to good vs. poor outcomes • fMRI may prove to be a useful clinical tool to assess relapse susceptibility

43. Methamphetamine Abuse, HIV Infection Causes Changes in Brain StructureJernigan,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. • Co-occurring methamphetamine abuse and HIV infection appears to result in greater impairment than each condition alone

44. Methamphetamine Abuse, HIV Infection Causes Changes in Brain StructureJernigan,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. • They also assessedthe 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.

45. Methamphetamine Abuse, HIV Infection Causes Changes in Brain StructureJernigan,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). • 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

46. Methamphetamine Abuse, HIV Infection Causes Changes in Brain StructureJernigan,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,” • “The impact of methamphetamine could potentially affect treatment and relapse prevention efforts, as well as things like money management and driving performance.”

47. Methamphetamine Abuse, HIV Infection Causes Changes in Brain StructureJernigan,T, et al American Jnl of Psychiatry Aug 2005 • 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. • In methamphetamine abusers who are also HIV-positive, decreased volumes are correlated with increased cognitive impairment in one brain region, the hippocampus.