1. Medication Development for Methamphetamine Dependence
Keith Heinzerling, MD, MPH
David Geffen School of Medicine at UCLA
Department of Family Medicine
February 25, 2009

2. Medical Approach to Addiction Treatment: Three Components
Medications
Counseling (CBT, CM, etc.)
Support (NA, family, clergy, environment)

3. Anti-Addiction Medications
Medication actions:
Instill abstinence/reduce withdrawal- STOP
Prevent relapse- STAY STOPPED
FDA approved medications for addiction:
Smoking cessation (NRT, Zyban®, Chantix®)
Alcohol (Disulfiram, naltrexone, acamprosate)
Opioids (Buprenorphine or Suboxone®)
No approved medications available for:
Cocaine, Marijuana, METHAMPHETAMINE
Clinical trials to develop medications

4. Clinical Practice- Approved Medications
Addiction Medicine Clinic
at the UCLA Family Health
Center in Santa Monica
Research- Clinical Trials of Potential Medications for Methamphetamine Dependence
Methamphetamine clinical trials
in Hollywood (adults)
and East Los Angeles (adolescents)

6. Baseline meth use frequency is strongest predictor of treatment outcome
Working memory, reaction time not significantly associated with abstinence in CART model

7. Baseline meth use also influences treatment completion

9. Bupropion for MA Dependence: Reverse Dopamine Dysfunction?
Bupropion is a reuptake inhibitor for dopamine and norepinephrine:
Increase in dopamine may counter-act methamphetamine-induced deficits in dopminergic function
Bupropion has clinical activity that may help in methamphetamine dependence:
Depression (Wellbutrin®)
Smoking Cessation (Zyban®)
ADHD
Early studies for cocaine dependence

10. Results: No Difference in Retention

11. Results: No Difference in MA Use Overall

12. Results: Bupropion Better Than Placebo Among Low Frequency MA Users
Light MA Users: 0 to 2 of 6 baseline urine drug screens positive for MA

13. Results: No Difference in MA Use Among High Frequency MA Users
Heavy MA Users: 3 to 6 of 6 baseline urine drug screens positive for MA

14. Results: Secondary Outcomes
No difference in depressive symptoms (BDI scores)
No difference in MA cravings (visual analog scale)
Reductions in cigarette smoking significantly greater in bupropion group compared to placebo (positive control)

15. Bupropion for MA Dependence- Conclusions
Bupropion may be effective for MA dependence, but only among low frequency MA users
Similar result in other recent trial (Elkashef AM, et. Al., 2007)
Follow-up study in adults (with genetics) currently recruiting in Hollywood
Follow-up study in adolescent meth users currently recruiting in East Los Angeles

17. Modafinil: Non-amphetamine type stimulant
Provigil ®
Brightens mood
Promotes wakefulness/ counters fatigue
Cognitive effects, impulse control
Improved SSRT in Healthy Control Subjects
SSRT Deficit in Meth Abusers *
Meth
control
DC Turner et al. , Psychopharmacology, 2003
London lab, current study

18. Previous Studies of Modafinil for MA and Cocaine Dependence
Modafinil blocks cocaine subjective effects and self-administration in human lab studies (Dackis et al., 2003; Malcolm et al., 2006; Hart et al., 2008)
Two randomized, double-blind, placebo-controlled trials with reductions in cocaine use (Dackis et al., 2005, Dackis et al., 2007)
but not co-morbid cocaine/alcohol dependence
Double-blind, placebo-controlled trial of 200 mg daily (Shearer et al., 2009)
No significant effect on retention, MA positive urines overall but trend in highly med adherent participants

19. Beneficial Effects of Modafinil on Cognitive Function
Modafinil improves working memory, executive function, and response inhibition
Adults with ADHD (Turner et al., 2004)
Schizophrenics (Turner et al., 2004)
Healthy adults (Turner et al., 2003)
Deficits in cognitive function (Scott et al., 2007) and response inhibition (Monterosso et al., 2005) in MA users
Decreased retention in CBT among cocaine users with lower cognitive function (Aharonovich et al., 2006) >> Modafinil may improve cognition and thereby increase retention

20. Survival Analysis
X2 = 0.80, d.f. = 1, p = 0.37

21. Survival Analysis- High Frequency MA Users
X2 = 1.99, d.f. = 1, p = 0.16

22. Survival Analysis- Low Frequency MA Users
X2 = 0.04, d.f. = 1, p = 0.84

23. Study Retention 57 46 54 37 59 53 41% 35% 40% 20% 42% 45% 14 13 6 3 8
Total Sample
HIGH Freq. User
LOW Freq. User
MOD
(N=34)
PLA
(N=37)
(N=15)
(N=19)
(N=22)
Days retained 57 46 54 37 59 53
Completed, %
41%
35%
40%
20%
42%
45%
Completed, N 14 13 6 3 8 10
But differences in retention/completion not statistically significant

24. Proportion of Urine Screens that were MA-free
GEE model: X2 = 0.13, p = 0.72

25. MA-free Urine Screens- High Frequency MA Users
GEE model OR
95% CI
Treatment
1.08
Baseline Use
7.23

26. MA-free Urine Screens- Low Frequency MA Users
GEE model OR
95% CI
Treatment
1.08
Baseline Use
7.23

27. Aggregate Urine Drug Screen Results
Total Sample
HI Freq User
LOW Freq User
MOD
(N=34)
PLA
(N=37)
(N=15)
(N=19)
(N=22)
Joint Probability Index
Week 6
0.53
0.43
0.33
0.27
0.68
0.54
Week 12
0.35
0.30
0.13
0.37
0.41
Treatment Effectiveness Score
13.1
12.7
8.3
5.2
16.9
17.9
Longest MA abstinence, days 18 17 12 7 23 24
Final two weeks abstinent
27%
13% 8%
37%
41%

28. Meth using participants have mild cognitive impairment
MicroCog Index Score
Mean
(Std. Dev.)
General Cognitive Functioning
64.85 (18.40)
General Cognitive Proficiency
89.75 (13.48)
Information Processing Speed
96.11 (14.70)
Information Processing Accuracy
85.39 (16.97)
Attention/Mental Control
92.99 (15.37)
Reasoning/Calculation
87.92 (16.43)
Memory
93.45 (14.97)
Spatial Processing
(11.42)
Reaction Time
(14.70)
Reference Norms in Healthy Adults
(15.00)

29. Cognitive impairment is associated with treatment drop-out
Completed
(N=27)
Mean
(Std. Dev.)
Did not complete (N=44)
≥ 2 weeks MA abstinence (N=28)
< 2 weeks MA abstinence (N=43)
General Cognitive Functioning
68.6 (4.1)
62.6 (2.5)
63.0 (2.7)
66.0 (3.2)
General Cognitive Proficiency
94.0 (2.9) a
87.1 (1.8) a
90.2 (2.7)
89.4 (2.0)
Information Processing Speed
98.1 (2.7)
94.9 (2.3)
96.0 (2.8)
96.2 (2.2)
Information Processing Accuracy
89.9 (3.2) b
82.6 (2.5) b
86.2 (3.2)
84.9 (2.6)
Attention/Mental Control
95.3 (3.3)
91.6 (2.2)
91.6 (3.3)
93.9 (2.1)
Reasoning/Calculation
92.1 (3.4) b
85.3 (2.3) b
90.7 (3.6)
86.1 (2.2)
Memory
96.1 (3.2)
91.8 (2.1)
93.1 (3.1)
93.7 (2.2)
Spatial Processing
103.8 (2.4)
102.1 (1.6)
102.4 (2.4)
103.0 (1.6)
Reaction Time
102.6 (2.9)
101.3 (2.2)
101.3 (2.9)
102.2 (2.2)
a p < 0.05; b p < 0.10

30. Modafinil- Conclusions
No significant effect for modafinil (400 mg daily) over placebo overall
Post-hoc analysis: retention significantly longer with modafinil compared to placebo among baseline HIGH, but not LOW frequency, MA users
Cognitive function influences treatment outcome- ? Effect of modafinil
Future studies of modafinil in baseline high frequency MA users may be warranted

32. Sustained release d-amphetamine for Meth dependence
Severe Meth dependence:
Meth use on 3+ days/week; mostly IV users
14 day stabilization period:
initial dose of d-amphetamine 20 mg/day, increased by 10 mg daily as required until stabilized or to a maximum of 110 mg/day
Supervised dosing daily at community pharmacies for 3 months
43% of participants attended ZERO counseling sessions

33. Retention was significantly longer for d-amphetamine
Treatment
Mean (S.D.)
D-amphetamine
86.3 days (52.2 days)
Placebo
48.6 days (45.4 days)

34. Trend for lower self-reported meth use with d-amphetamine (p=0.086)
No significant difference in meth in hair samples
Lower meth dependence symptoms for d-amphetamine (p=0.04)

35. Conclusions: Sustained release d-amphetamine
May be a future option for patients with severe methamphetamine dependence
Daily supervised dosing would be an obstacle to treatment dissemination
Reluctance to duplicate methadone program experience
May have utility in inpatient/residential setting
Increased retention > reduction in use
Agonist approach warrants further investigation

37. Naltrexone for Amphetamine Dependence
Mu opioid receptor blocker
FDA approved for alcohol dependence
Monthly injection: Vivitrol®
Participants had to abstain from amphetamine use for 2 weeks prior to randomization
Testing as relapse prevention agent?
Results may not apply in those who cannot achieve initial abstinence

38. Naltrexone may be effective for relapse prevention in meth users
Naltrexone group had a significantly higher mean number of amphetamine-
negative urine samples than the placebo group (F=5.02, df=1, 78, p<0.05).
The mean percentage of negative urine samples during the 12-week trial was 65.2% (SD=36.1) for the naltrexone group and 47.7% (SD=33.7) for the placebo group.
The mean number of negative tests until a relapse occurred was 12.5 (SD=1.6) for the naltrexone group and 6.3 (SD=1.1) for the placebo group (t=6.36, p<0.05 for survival analysis)
Naltrexone may be effective for relapse prevention in meth users

39. Conclusions / Future Directions:
One treatment does not fit all:
Bupropion for intermittent meth users
Modafinil for daily or near daily meth users or those with cognitive impairment?
D-amphetamine with supervised dosing for most severely dependent patients?
Naltrexone for relapse prevention following inpatient detoxification?
Two stage treatments: detoxification followed by relapse prevention?
Possible genetic influences on treatment response?

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