Methamphetamine: New Knowledge, Neurobiology and Clinical Issues

1. Methamphetamine: New Knowledge, Neurobiology and Clinical Issues Richard A. Rawson, Ph.D 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) Pacific Southwest Technology Transfer Center (SAMHSA) International Network of Treatment and Rehabilitation Resource Centres (UNODC)

2. Stimulants COCAINE CRACK METHAMPHETAMINE

3. Stimulants Description: A group of synthetic and plant-derived drugs that increase alertness and arousal by stimulating the central nervous system. Medical Uses: Short-term treatment of obesity, narcolepsy, and hyperactivity in children Method of Use: Intravenous, intranasal, oral, smoking

4. Types of Stimulant Drugs Cocaine Products • Cocaine Powder (Generally sniffed, injected, smoked on foil) • “Crack” (smoked) • Major areas of use: South America; USA (predominantly major urban centers, disproportionately impacts African American community); Increasing in Europe.

5. Types of Stimulant Drugs Amphetamine Type Stimulants (ATS) • Amphetamine “Speed” • Dexamphetamine “Ice” • Methylphenidate “Crank” • Methamphetamine “Yaba” “Shabu”

6. Methamphetamine vs. Cocaine • Cocaine half-life: 1-2 hours • Methamphetamine half-life: 8-12 hours • Cocaine paranoia: 4 -8 hours following drug cessation • Methamphetamine paranoia: 7-14 days • Methamphetamine psychosis - May require medication/hospitalization and may not be reversible • Neurotoxicity: Appears to be more profound with amphetamine-like substances

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

8. 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

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

10. A Major Reason People Take a Drug is they Like What It Does to Their Brains

13. FOOD SEX 200 200 NAc shell 150 150 DA Concentration (% Baseline) 100 100 15 % of Basal DA Output 10 Empty Copulation Frequency 50 Box Feeding 5 0 0 Scr Scr Scr Scr 0 60 120 180 Bas Female 1 Present Female 2 Present Mounts Time (min) Sample Number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Intromissions Ejaculations Source: Di Chiara et al. Source: Fiorino and Phillips Natural Rewards Elevate Dopamine Levels

14. Effects of Drugs on Dopamine Release 1500 1000 500 0 COCAINE METHAMPHETAMINE Accumbens 400 Accumbens DA 300 DOPAC HVA % of Basal Release % Basal Release 200 100 0 0 1 2 3hr Time After Cocaine Time After Methamphetamine 250 NICOTINE ETHANOL 250 Accumbens Dose (g/kg ip) 200 Accumbens 200 Caudate 0.25 0.5 150 % of Basal Release 1 2.5 % of Basal Release 150 100 0 1 2 3 hr 100 0 0 0 1 2 3 4hr Time After Nicotine Time After Ethanol Source: Shoblock and Sullivan; Di Chiara and Imperato

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

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

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

26. 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.

27. 33 year old man, high on methamphetamine admitted to emergency room complaining of severe headache in Portland Oregon. • X-ray revealed 12, 2 inch nails (6 on each side) in his head, administered with aq nail gun. • 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

28. 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.

29. Cardiac Disorders and MA Use • Coronary Syndromes • Arrhythmia • Cardiomyopathy • Hypertension • Valvular Disease

30. Neurologic Disorders and MA Use • Headache • Seizure • Cerebrovascular • Ischemic stroke • Cerebral hemorrhage • Cerebral vasculitis • Cerebral edema

31. Respiratory Disorders and MA Use • Pulmonary edema • Bronchitis • Pulmonary hypertension • COPD

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

35. MethamphetaminePsychiatric Consequences • Paranoid reactions • Long term memory loss • Depressive reactions • Hallucinations • Psychotic reactions • Panic disorders • Rapid addiction

36. MA Psychosis Inpatients from 4 Countries

37. 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 flashbacksYui et al., 2001 • Polymorphism in DAT Gene associated with MA psychosis in Japanese Ujike et al., 2003

38. Treatment

39. Is Treatment for Methamphetamine Effective? • A pervasive rumor has surfaced in many geographic areas with elevated MA problems: • 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.

40. Why the “MA Treatment Does Not Work” Perceptions? • Many of the geographic regions impacted by MA do not have extensive treatment systems for severe drug dependence. • Medical and psychiatric aspects of MA dependence exceeds program capabilities. • High rate of use by women, their treatment needs and the needs of their children can be daunting. • Although some traditional elements may be appropriate, many staff report feeling unprepared to address many of the clinical challenges presented by these patients

41. 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

42. Statistics Analysis of: • Drop out rates • Retention in treatment rates • Re-incarceration rates • Other measures of outcome All these measures indicate that MA users respond in an equivalent manner as individuals admitted for other drug abuse problems. • Analysis of data from 3 other large data sets and 3 clinical trials data sets suggest treatment response (using psychosocial treatments) of MA and cocaine users is indistinguishable.

43. Additional Information on Population

44. Mean Days of Primary Drug Use in Last 30 Days

45. Bupropion: An Efficacious Pharmacotherapy? • Newton et al., (2005): • Bupropion reduces craving and reinforcing effects of meth • Elkashef (recently completed): • Bupropion reduces meth use in an outpatient trial, with particularly strong effect with less severe users.

46. Special Treatment Consideration Should Be Made for the Following Groups of Individuals: • Female MA users (higher rates of depression; very high rates of previous and present sexual and physical abuse; responsibilities for children). • Injection MA users (very high rates of psychiatric symptoms; severe withdrawal syndromes; high rates of hepatitis). • MA users who take MA daily or in very high doses. • Homeless, chronically mentally ill and/or individuals with high levels of psychiatric symptoms at admission. • Individuals under the age of 21. • Gay men (at very high risk for HIV and hepatitis).

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

48. Contingency Management for treatment of methamphetamine dependence • Design: RTC • Method: 113 patients diagnosed with methamphetamine abuse or dependence were randomly assigned to receive either treatment as usual (TAU) or TAU plus contingency management. • Results indicate that both groups were retained in treatment for equivalent times but those in the combined group accrued more abstinence and were abstinent for a longer period of time. These results suggest that contingency management has promise as a component in methamphetamine use disorder treatment strategies. • Contingency Management for the Treatment of Methamphetamine Use Disorders. Roll, JM et al, Archives of General Psychiatry, (In Press)

49. Cognitive Behavioral Therapy and Contingency Management for Stimulant Dependence • Design Randomized clinical trial. • Participants Stimulant-dependent individuals (n = 171). • Intervention CM, CBT, or combined CM and CBT, 16-week treatment conditions. CM condition participants received vouchers for stimulant-free urine samples. CBT condition participants attended three 90-minute group sessions each week. CM procedures produced better retention and lower rates of stimulant use during the study period. • Results Self-reported stimulant use was reduced from baseline levels at all follow-up points for all groups and urinalysis data did not differ between groups at follow-up. While CM produced robust evidence of efficacy during treatment application, CBT produced comparable longer-term outcomes. There was no evidence of an additive effect when the two treatments were combined. The response of cocaine and methamphetamine users appeared comparable. • Conclusions: This study suggests that CM is an efficacious treatment for reducing stimulant use and is superior during treatment to a CBT approach. CM is useful in engaging substance abusers, retaining them in treatment, and helping them achieve abstinence from stimulant use. CBT also reduces drug use from baseline levels and produces comparable outcomes on all measures at follow-up. • Rawson, RA et al. Addiction, Jan 2006

50. Contingency Management: A Meta-analysis • A recent meta-analysis reports that CM results in a successful treatment episode 61% of the time while other treatments with which it has been compared result in a successful treatment episode 39% of the time (Prendergast, Podus, Finney, Greenwell & Roll, submitted)