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
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: 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 OH CH CH 3 3

8. Scope of the Methamphetamine Problem Worldwide
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

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

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

13. Natural Rewards Elevate Dopamine Levels50
100
150
200 60
120
180
Time (min)
% of Basal DA Output
NAc shell
Empty
Box
Feeding
Source: Di Chiara et al.
FOOD
100
150
200
DA Concentration (% Baseline)
Mounts
Intromissions
Ejaculations 15 5 10
Copulation Frequency
Sample
Number 1 2 3 4 6 7 8 9 11 12 13 14 16 17
Scr
Bas
Female 1 Present
Female 2 Present
Source: Fiorino and Phillips
SEX

14. Effects of Drugs on Dopamine Release
Time After Methamphetamine
% Basal Release
METHAMPHETAMINE 1 2
3hr
1500
1000
500
Accumbens
100
200
300
400
Time After Cocaine
% of Basal Release DA
DOPAC
HVA
Accumbens
COCAINE
100
150
200
250 1 2
3 hr
Time After Nicotine
% of Basal Release
Accumbens
Caudate
NICOTINE
100
150
200
250 1 2 3
4hr
Time After Ethanol
% of Basal Release
0.25
0.5
2.5
Accumbens
Dose (g/kg ip)
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
If DAT is decreased in young METH users (almost to that observed in Parkinson’s Disease), and DAT decreases with age, may we see an increase in the number of Parkinsonian patients over time?
Control Methamphetamine PD
Source: McCann U.D.. et al.,Journal of Neuroscience, 18, pp , October 15, 1998. .

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

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

29. Long-term effects of stimulants
Strokes, seizures, and headaches
Irritability, restlessness
Depression, anxiety, irritability, anger
Memory loss, confusion, attention problems
Insomnia
Paranoia, auditory hallucinations, panic reactions
Suicidal ideation
Sinus infection
Loss of sense of smell, nosebleeds, chronic runny nose, hoarseness
Dry mouth, burned lips
Worn teeth (due to grinding during intoxication)
Problems swallowing
Chest pain, cough, respiratory failure
Disturbances in heart rhythm and heart attack
Gastrointestinal complications (abdominal pain and nausea)
Loss of libido
Malnourishment, weight loss, anorexia
Weakness, fatigue
Tremors
Sweating
Oily skin, complexion

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

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

32. Respiratory Disorders and MA Use
Pulmonary edema
Bronchitis
Pulmonary hypertension
COPD

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

36. Methamphetamine Psychiatric Consequences
Paranoid reactions
Long term memory loss
Depressive reactions
Hallucinations
Psychotic reactions
Panic disorders
Rapid addiction

37. MA Psychosis Inpatients from 4 Countries
No. of patients having symptoms (%)
Psychotic symptom
Lifetime
Current
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)
Srisurapanont et al., 2003

38. 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

39. Treatment

40. 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.

41. 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

42. Meth. Treatment Statistics
During the 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

43. 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.

44. Additional Information on Population

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

46. 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.

47. 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).

48. 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.

49. 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)

50. 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

51. 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)

52. Matrix Model in Treatment of Methamphetamine Depenence
Design: The study was conducted as an eight-site randomized clinical trial.
Method: 978 treatment-seeking, MA-dependent persons were randomly assigned to receive either TAU at each site, or a manualized 16-week treatment (Matrix Model) for their MA dependence.
Results: Analyses of study data indicate that in the overall sample, and in the majority of sites, those who were assigned to Matrix treatment attended more clinical sessions, stayed in treatment longer, provided more MA-free urine samples during the treatment period, and had longer periods of MA abstinence than those assigned to receive TAU. Measures of drug use and functioning collected at treatment discharge and 6 months post-admission indicate significant improvement by participants in all sites and conditions when compared to baseline levels, but the superiority of the Matrix approach did not persist at these two time points.
Conclusions: Study results demonstrate a significant initial step in documenting the efficacy of the Matrix approach. Although the superiority of the Matrix approach over TAU was not maintained at the posttreatment time points, the in-treatment benefit is an important demonstration of empirical support for this psychosocial treatment approach.
Rawson, R et al Addiction vol 99, 2004

53. Mean Number of Weeks in Treatment

54. Mean Number of UA’s That Were MA-free During Treatment

55. Urinalysis Results
Results of Ua Tests at Discharge, 6 months and 12 Months post admission**
Matrix Group TAU Group
D/C: % MA-free % MA-free
6 Ms: % MA-free % MA-free
12 Ms: 59% MA-free % MA-free
**Over 80% follow up rate in both groups at all points

56. 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-Age).
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).

57. Adolescent Meth. Abuse Treatment Admissions
Matrix (Boys) (Girls)
% 63%
% 67%
% 69%
Phoenix (Boys) (Girls)
% 43%
% 51%
% 53%

58. Drug Courts and Methamphetamine Users
Recently the marketing material for an experimental methamphetamine procedure costing $15,000 has reported what they considered extraordinarily high rates (98%+) of drug free urine specimens in 2 “pilot trials” in drug court programs in Michigan and Washington State.
An examination was conducted of the urinalysis data from 2 California drug court programs using more traditional treatments.
In one program treating 70% meth users in Rancho Cucamonga Calif, over a 6 year period and over 40,000 urine samples, the rate of drug free samples was 96.5%
In a second drug court program in Hayward, California, over a 2 year period, with exclusively and meth population, the rate of drug free urine samples was 97.2%.

59. My Sexual Pleasure is Enhanced by the use of:
(Rawson et al., 2002)

60. My Sexual Performance is Improved by the use of:
(Rawson et al., 2002)

61. Behavior Symptom Inventory (BSI) Scores at Baseline

62. Route of Methamphetamine Administration
Smoking (SM) was the most common route of MA administration (n=632, 65%), followed by injecting (IDU) (n=228, 23.4%) and intranasal (IN) (n=113, 11.6%).

63. BSI Psychiatric Symptoms by Route
Positive Symptom Total (PST)
Results from the BSI show that IDUs were more psychologically impaired across all nine dimensions and three global indices of the BSI before entering treatment and after exiting tx compared to SMs and INs
The Brief Symptom Inventory (BSI) is a 53-item self-report symptom inventory used to assess psychological symptoms across nine dimensions and three global indices of distress. The nine symptom dimensions include: somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism, and the three global indices include: the Global Severity Index (measuring overall psychological distress level), the Positive Symptom Distress Index (measuring the intensity of symptoms), and the Positive Symptom Total (measuring the number of self-reported symptoms).
P<.05

64. Hepatitis C by Route P<.05
To date, three-year follow-up medical testing data reveal that approximately 28 of the 979 MA users are carriers of the Hepatitis C virus. Results showed that these rates of Hepatitis C significantly differed by route of administration, such that the majority of Hepatitis C cases were diagnosed among injectors (74.1%; n=21, compared to smokers (22.2%; n=6) and intranasal users (3.7%; n=1).
P<.05

65. Methamphetamine Abuse: Treatment as Prevention Richard A
Methamphetamine Abuse: Treatment as Prevention Richard A. Rawson, Cathy J. Reback, Steven Shoptaw UCLA Integrated Substance Abuse Programs

66. Overview
Substance abuse concomitant with risky sex for MSM (Stall & Wiley, 1988)
Different drugs have differing prevalence of HIV among MSM
Drug abuse treatments dramatically reduce methamphetamine use and high-risk sex
Reductions are sustained!
Policy implications
Substances have long been used by members of the gay and bisexual male communities to enhance sexual functioning. Prior to meth, it was cocaine. Poppers continue to be used. These substances are used to cover feelings of shame and homophobia around having sex, to cover fatigue from dealing with HIV infections (whether one is already positive or one is negative, but engaging in risk behaviors periodically so always anxious about becoming positive) and to facilitate a type of extreme sexual behavior that is not available when not medicated (not enough energy to sustain hours to days of continuous sexual behaviors). While substances have been used for a long time, different drugs of abuse have differences in prevalence for HIV among MSM. We provide data on a study that shows reductions in meth use and high risk sex and end with policy implications of this work.

67. Sex Risks Reduced with Treatment: UARI Past 30 Days

68. Summary
Use of psychostimulants is a significant public health problem in the US.
In California (and worldwide), methamphetamine is and has been for some time the most widely used illicit drug other than cannabis.
Cocaine and methamphetamine produce many similar acute and chronic effects.
Psychosocial treatments currently have greatest empirical support, although research on pharmacotherpies is promising.

69. Thank you rrawson@mednet. ucla. edu www. uclaisap. org www
Thank you