1. Current Perspectives on Medication Development for Methamphetamine Dependence Steve Shoptaw January 5, 2006

2. Key Points Acute Symptoms vs Abuse/dependence Mechanism vs syndromic approach Medications with promise for other stimulants may work for methamphetamine New directions – bupropion

3. Acute Symptoms Intoxication and psychotic symptoms can be managed efficiently using current medications – Benzodiazepine +/- short and fast acting antipsychotics Medical consequences present more challenging medical management Objective is resolution of symptoms; stabilize patient

4. Risperidone/Haloperidol Controlled evaluation of risperidone (.75mg) and haloperidol (3mg) among healthy volunteers Placebo-controlled, 2 (treatment agent) x 2 (meth 20mg or placebo) design Active drugs caused mild sedation compared to placebo Neither drug blocked subjective effects of methamphetamine Wachtel et al., 2002 Thus, acute meds unlikely to have long lasting effects for Rx!

5. Abuse and Dependence Treatment targets –Instilling of abstinence –Prevention of relapse –Improve mood and cognition –Reduce craving Pharmacology of methamphetamine associated with use patterns complicates medication development

6. Prefrontal Cortex Thalamus Nuc Accumbens Substantia Nigra Subthalamic Nuclei Globus Pallidus High Affinity D2 receptor loop Low Affinity D1 receptor loop

7. Important Neuropharm Considerations High dose (5-10mg/kg) – D2 mediated –Enters cell via passive diffusion –Reverse transporters (DAT, 5-HT, NE, VMAT- 2) –Affects transporter trafficking (DAT) by entering vesicles Leads to abnormal monoamine distribution Generates free radicals

8. High Dose Methamphetamine >10 fold presynaptic increase of monoamines Activates D1 receptor and D2 receptors Toxicity to some DA and 5HT pathways, but NOT NE –Amphet damages DA; MA damages DA & 5-HT; MDMA damages 5-HT May damage some interneurons, NPY, somatostatin and is D-1 sensitive If dose starts low and escalates gradually, causes “tolerance”

9. Low Dose Methamphetamine Low dose (.5-1mg/kg) – D1 mediated and is within therapeutic dose –Enters cell by riding plasma-lemnal transporters –Reverses transporters, largely by blocking uptake –Mostly D-1 effects, but some D2 –Little or no metabolic problems, so no free radicals

10. Pharmacology of Methamphetamine Targets (D1 or D2, 5-HT) may vary by use level and previous history Neuropeptide-related systems that may be affiliated with low dose, D1 effects –GABA (+/- glutamate) –Nicotinic receptor –VMAT-2 –CB-1 antagonist

11. Mechanistic Precursor Approach While not a Phase 2 trial, placebo-controlled double- blind cross-over evaluation of tyrosine-free amino acid mixture 4 h before methamphetamine challenge in 16 healthy volunteers Tyrosine-free mixture caused significant reductions in subjective and objective measures of stimulant effects of methamphetamine (McTavish et al., 2001)

12. Amlodipine Randomized, placebo- controlled, double- blind 8-week study Amlodipine –10m/d (n=26) –5mg/d (n=25) –Placebo (n=26) No differences between groups by urine drug screening, self-report of drug use, craving or severity of dependence Batki et al., 2001 (unpublished data) Mechanism - Calcium Channel Blocker

13. This just in on mechanisms… 20 week trial of Concerta, aripiprazole, placebo in IV 53 methamphetamine abusers in Norway Concerta (methylphenidate SR) significantly better than placebo; Aripiprazole significantly worse than placebo CTN Meth Menace Conference, 12/2005

14. A Syndrome Approach… Enhanced Job Functioning Euphoria/Partying Psychiatric/Cognitive Effects

15. Psychiatric Medications Fluoxetine Imipramine Sertraline Gabapentin Baclofen

16. Fluoxetine Randomized, placebo- controlled, double- blind, 8-week study Fluoxetine 40mg/d, n=32; placebo n=28 No differences between groups by urine drug screen, self- report of drug use, craving Batki et al., 2000 (CPDD abstract) Mechanism – SSRI; Mediate depression

17. Imipramine High dose outperformed low dose for retention (p<.05) No differences in methamphetamine use, depression or craving ratings Galloway et al., 1996 Mechanism – Tricyclic Antidepressant

18. Sertraline Study Design Randomized, double blind, placebo-controlled trial for 225 participants, using a 2x2 design Sertraline (Zoloft) - start at 50 mg/day; increase to 100 mg/day after 1 week [versus placebo] Contingency Management – Higgins’ high magnitude voucher reinforcement [versus no CM] 12 weeks, thrice weekly urine drug screening and group counseling sessions

19. Demographics Gender 39% Female Race 73% Caucasian 24% Hispanic 2% Asian 1% Afr-Amer Age, in years 33.0 (7.2) Education, in years 12.0 (1.6)

20. Methamphetamine Use Any Past Treatment40.0% Route of Use Snort Smoke IV 13.8% 65.8% 20.4% Days used in past month13.0 (9.0) Years used in lifetime Longest Abstinence 9.4 (5.6) 9.2 (14.8)

21. Retention n.s effects CM n.s effects Med Number of Patients Surviving

22. Treatment Effectiveness Scores CM: F = 8.6, df = 1, p < 0.01 Medication n.s.

23. Longest Abstinence CM: F = 25.4, df = 1, p < 0.001 Medication n.s.

24. Urine Drug Screening: Sertraline Proportion Meth Positive Zoloft + no CM All Others

25. Conclusions on Sertraline; SSRIs? CM effective at reducing methamphetamine abuse (longest abstinence; TES) Placebo effective over sertraline along abstinence variables No real effect of depression reduction –Implications on using SSRI medications for methamphetamine abuse

26. Gabapentin Baclofen

27. Study Design Gabapentin 800mg tid Baclofen 20mg tid Placebo tid Thrice Weekly Matrix Model Counseling 2 week non- med baseline 16 week medication trial Randomization

28. Demographics Baclofen (n=25) Gabapntn (n=26) Placebo (n=37) Age33.0 (8.2)32.4 (7.3)31.4 (8.1) Education*12.5 (1.8)10.8 (2.8)12.7 (1.8) *p < 0.05

29. Demographics Baclofen (n=25) Gabapntn (n=26) Placebo (n=37) Gender Female Male 28% 72% 38% 62% 27% 73% Ethnicity White Latino/a Other 72% 20% 8% 54% 31% 15% 54% 38% 8%

30. Drug Use History Baclofen (n=25) Gabapntn (n=26) Placebo (n=37) 30-Day Meth 13.8 (8.1)16.6 (10.2)14.4 (8.8) Meth Lifetime8.9 (7.4)10.1 (6.3)9.6 (5.9) 30-Day Cocaine0.6 (3.0)0.3 (1.2)0.1 (0.5) 30-Day Marijuana*8.9 (11.6)2.4 (6.1)3.3 (6.6) P < 0.05

31. Route of Administration

32. Survival Analysis

33. Completers F(2,84)=5.45, p=0.006; Baclofen vs Placebo p=0.002; Gabapentin vs Placebo p=0.06

34. Medication Compliance

35. Urine Drug Screening: Composites

36. Medication by Compliance

37. Depression P = 0.057

38. Depression and Methamphetamine

39. Baclofen/Gabapentin: Summary Education and Cannabis differences by assignment No significant main effects for treatment condition Post hoc analyses suggests baclofen effects, particularly with increased medication compliance More evidence of a need for “super GABA” agent –Open label trial of Brodie et al (2005)

40. Partying: Ondansetron 5-HT3 antagonist with evidence of efficacy for early-onset alcoholism (Johnson et al., 2004) MCTG study completed in 2004 1,2,4,0mg/d No evidence of any dose of ondansetron over placebo as measured by methamphetamine use, retention, craving (Johnson et al., 2004 CPDD abstract)

41. What’s New in The Medication Cupboard? Recent Findings: –Bupropion Significant effect on urine, especially in low use group Planned Studies –Bupropion –GVG –Modafinil

42. Application of Advanced Biostatistics Random Effect Markov Transition Models Shoptaw, Yang et al., 2002

43. Design Improvements Using contingency management to instill abstinence for relapse prevention meds Characterization of baseline predictors of treatment outcomes