1. Methamphetamine: The Nature of the National Epidemic 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: National Institute on Drug Abuse (NIDA) National Institute on Drug Abuse (NIDA) Pacific Southwest Technology Transfer Center (SAMHSA) Pacific Southwest Technology Transfer Center (SAMHSA)

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.

3. 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’

4. EPHEDRINE OHOH CC HHH 3 CH 3 N

5. Methamphetamine The US Epidemic

6. According to surveys and estimates by WHO and UNODC, methamphetamine is the most widely used illicit drug in the world except for cannabis. World wide it is estimated there are over 26 million regular users of amphetamine/methamphetamine, as compared to approximately 16 million heroin users and 14 million cocaine users Scope of the Methamphetamine Problem Worldwide

7. Meth Epidemic; less drama, more long term risk/danger Cocaine/Crack epidemic hit fast (in NYC 1986-87, as well as other major east coast cities); overnight emergency, tremendous media attention. Big federal response (Reagan and Bush I). High visibility deaths, stigmatization as a ghetto drug. Dramatic decreases in indicators by early 1990s, except in inner cites of east coast. Crack epidemic: Rapid onset; Rapid decrease Meth epidemic: Slow west to east spread. No decrease in western cities. Use becomes endemic?

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

9. 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).

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

11. The Eastward Spread of Methamphetamine

12. Primary Amphetamine/Methamphetamine TEDS Admission Rates: 1992 (per 100,000 aged 12 and over) 35 - 58 12 - 35 < 12 No data > 58

13. < 12 Primary Amphetamine/Methamphetamine TEDS Admission Rates: 1997 (per 100,000 aged 12 and over) 35 - 58 12 - 35 < 12 No data > 58

14. Primary Amphetamine/Methamphetamine TEDS Admission Rates: 2003 (per 100,000 aged 12 and over) 127+ < 5 5 - 59 60-126 Incomplete Data

15. Inter-generational Use & Cooking

16. 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

17. Methamphetamine: A Growing Menace in Rural America In 1998, rural areas nationwide reported 949 methamphetamine labs. Last year, 9,385 were reported. This year, 4,589 rural labs had been reported as of July 26. Source: El Paso Intelligence Center (EPIC), U.S. DEA

18. Methamphetamine Acute Physical Effects - Increases -Decreases Heart rate Appetite Blood pressure Sleep Pupil size Reaction time Respiration Sensory acuity Energy

19. Methamphetamine Acute Psychological Effects Increases – Confidence – Alertness – Mood – Sex drive – Energy – Talkativeness Decreases – Boredom – Loneliness – Timidity

20. Methamphetamine Chronic Physical Effects - Tremor - Sweating - Tremor - Sweating - Weakness - Burned lips; sore nose - Dry mouth - Oily skin/complexion - Weight loss - Headaches - Cough - Dental Problems - Sinus infection - Anorexia

21. Prenatal Meth Exposure Preliminary findings on infants exposed prenatally to methamphetamine (MA) and nonexposed infants suggest… –Prenatal exposure to MA is associated with an increase in SGA (small for gestational size). –Neurobehavioral deficits at birth were identified in NNNS (Neonatal Intensive Care Unit Network Neurobehavioral Scale) neurobehavior, including dose response relationships and acoustical analysis of the infant’s cry. Lester et al 2005

24. Source: The New York Times, June 11, 2005. “ METH Mouth ” METH Use Leads to Severe Tooth Decay

25. Meth Use in Hawaii As of the middle of May, not even halfway through the year, the city medical examiner's office already recorded 38 deaths connected to crystal methamphetamine. So, we're well on the way to exceeding last year's total of 68. Deaths: Deaths: 2005 (mid-May) - 38 deaths 2004 - 68 deaths 2003 - 56 deaths 2002 - 62 deaths 2001 - 54 deaths 2000 - 34 deaths

26. Trauma in MA Users MA + n (%) Non-MA n (%) p Intentional 21 (37%) 34 (22%) <.04 Admitted 52 (91%) 108 (70%).001 Mean (SEM) LOS (days) 2.7 (0.4) 1.7 (0.1).003 Charges 15,617 (1866) 11,600 (648).01 Tominanga et al., 2004

27. Adolescent Meth Abuse Treatment Admissions Matrix (Boys) (Girls) –2002 16%63% –2003 25%67% –2004 22%69% Phoenix (Boys) –2002 25%43% –2003 23%51% –2004 27%53%

28. Methamphetamine Chronic Psychological Effects - Confusion - Irritability - Concentration - Paranoia - Hallucinations - Panic reactions - Fatigue - Depression - Memory loss - Anger - Insomnia - Psychosis

29. Methamphetamine Psychiatric Consequences Paranoid reactions Protracted memory loss Depressive reactions Hallucinations Psychotic reactions Panic disorders Rapid addiction

30. MA Psychosis Inpatients from 4 Countries Psychotic symptom LifetimeCurrent Persecutory delusion Auditory hallucinations Strange or unusual beliefs Thought reading Visual hallucinations Delusion of reference Thought insertion or made act Negative psychotic symptoms Disorganized speech Disorganized or catatonic behavior 130 (77.4) 122 (72.6) 98 (58.3) 89 (53.0) 64 (38.1) 56 (33.3) 35 (20.8) 75 (44.6) 39 (23.2) 27 (16.1) 38 (22.6) 20 (11.9) 18 (10.7) 36 (21.4) 19 (11.3) 14 (8.3) No. of patients having symptoms (%) Srisurapanont et al., 2003 Srisurapanont et al., 2003

31. MA Psychosis 69 physically healthy, incarcerated Japanese females with hx MA use –22 (31.8%) no psychosis –47 (68.2%) psychosis 19 resolved (mean=276.2±222.8 days) 8 persistent (mean=17.6±10.5 months) 20 flashbackers (mean=215.4±208.2 days to initial resolution) –11 single flashback –9 Recurrent flashbacks Yui et al., 2001 Polymorphism in DAT Gene associated with MA psychosis in Japanese Ujike et al., 2003 Ujike et al., 2003

32. 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

35. 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

36. 0 0 100 200 300 400 Time After Cocaine % of Basal Release DA DOPAC HVA Accumbens COCAINE 0 0 100 150 200 250 0 0 1 1 2 2 3 hr Time After Nicotine % of Basal Release Accumbens Caudate NICOTINE Source: Shoblock and Sullivan; Di Chiara and Imperato Effects of Drugs on Dopamine Release Time After Methamphetamine % Basal Release METHAMPHETAMINE 0123hr 1500 1000 500 0 Accumbens

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

38. 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 patients %ID/ cc. Control Methamphetamine PD

39. 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.

45. Methamphetamine: Neurochemical Mechanisms Methamphetamine enters the brain and is removed from the synapse by dopamine transporters

47. Methamphetamine: Neurochemical Mechanisms Enters dopamine vesicles Vesicles deplete themselves of dopamine

49. Methamphetamine: Neurochemical Mechanisms Free-floating DA produces “free radicals” (neurotoxins), so it is forced out of the neuron. The synapse is flooded with dopamine, producing a profound sense of pleasure.

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

52. Control > MA 4 3 2 0 1

53. MA > Control 5 4 2 0 1 3

54. 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.

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

56. 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.

57. 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.

58. Treatment Options

59. MA Treatment Issues Acute MA Overdose Acute MA Psychosis MA “Withdrawal” Initiating MA Abstinence MA Relapse Prevention Protracted Cognitive Impairment and Symptoms of Paranoia

60. MA “Withdrawal” - Depression- Paranoia - Fatigue- Cognitive Impairment - Anxiety- Agitation - Anergia- Confusion Duration: 2 Days - 2 Weeks

61. Meth Treatment Effectiveness? A pervasive rumor has surfaced in many geographic areas with elevated MA problems: MA users are virtually untreatable with negligible recovery rates. MA users are virtually untreatable with negligible recovery rates. Rates from 5% to less than 1% have been quoted in newspaper articles and reported in conferences. Rates from 5% to less than 1% have been quoted in newspaper articles and reported in conferences.

62. Meth Treatment Statistics During the 2002-2003 fiscal year: 35,947 individuals were admitted to treatment in California under the Substance Abuse and Crime Prevention Act funding. Of this group, 53% reported MA as their primary drug problem

63. Statistics A comparison of treatment outcomes between individuals diagnosed with methamphetamine dependence and all other diagnostic groups indicated no between group significant differences in any treatment outcome measures including: Retention in treatment rates Urinalysis data during treatment Rates of treatment program completion. All these measures indicate that MA users respond in an equivalent manner as individuals admitted for other drug abuse problems.

64. Comparability of Treatment Outcome: Cocaine vs Methamphetamine Huber, Ling and Rawson (Jnl of Addictive Diseases, 1997). Cohorts of methamphetamine dependent patients (N=500) and cocaine dependent patients (N=224) treated with a standardized, outpatient treatment protocol (Matrix Model) at the same clinic site, by the same staff over the same time period, demonstrated very similar treatment response on virtually all treatment participation and outcome measures

65. MA Users (n = 500) Cocaine Users (n = 224) Early Recovery Group + 3.4(4.4)3.7(3.3) Relapse Prevention Group + 23.7(29.0)21.0(26.8) Family Education Group + 11.6(14.0)12.2(12.8) Social Support Group + 4.4(14.9)4.3(18.2) Total of Treatment Hours Received + 52.9(51.4) 54.5(49.3) Weeks in Treatment + 17.1(22.3)18.0(21.3) Urine Sample Collected + 8.3(8.0)8.1(7.6) Percentage of Samples Positive for Primary Drug ++ 19.3% 13.3% Table 3. Treatment Experience to Methamphetamine and Cocaine Users { Treatment Received in Number of Hours } + Numbers presented are means and (standard deviations) ++ Numbers presented are percentages

67. Treatments for Stimulant-use Disorders with Empirical Support Cognitive-Behavioral Therapy (CBT) Community Reinforcement Approach Contingency Management 12 Step Facilitation All have demonstrated efficacy for the treatment of cocaine dependence

68. Methamphetamine Treatment: Controlled Clinical Trials –Brief Cognitive Behavioral Therapy –Extended Cognitive Behavioral Therapy –Contingency Management –Matrix Model

69. Summary Methamphetamine is a significant public health problem in the US and in the world It produces significant damage to the body and the brain Recovery from methamphetamine dependence is possible and most brain changes are reversible. There are effective treatments for methamphetamine dependence.