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

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

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

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)

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

Baseline meth use also influences treatment completion

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

Results: No Difference in Retention

Results: No Difference in MA Use Overall

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

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

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)

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

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

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

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

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

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

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

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

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

MA-free Urine Screens- High Frequency MA Users GEE model OR 95% CI Treatment 1.08 0.51-2.27 Baseline Use 7.23 3.38-15.43

MA-free Urine Screens- Low Frequency MA Users GEE model OR 95% CI Treatment 1.08 0.51-2.27 Baseline Use 7.23 3.38-15.43

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%

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 102.75 (11.42) Reaction Time 101.82 (14.70) Reference Norms in Healthy Adults 100.00 (15.00)

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

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

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

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)

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)

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

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

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

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?

866-449-UCLA THANK YOU! Questions or comments: Email me: heinzk@ucla.edu Page me: 310-825-6301, ext. 21764 On the web: www.uclasarx.org To refer a patient for medical treatment of addiction or to participate in a clinical trial: 866-449-UCLA