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Current Perspectives on Medication Development for Methamphetamine Dependence

Current Perspectives on Medication Development for Methamphetamine Dependence. Steve Shoptaw January 5, 2006. Key Points. Acute Symptoms vs Abuse/dependence Mechanism vs syndromic approach Medications with promise for other stimulants may work for methamphetamine New directions – bupropion.

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Current Perspectives on Medication Development for Methamphetamine Dependence

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

  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. 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 Amlodipine 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. 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 Fluoxetine Mechanism – SSRI; Mediate depression Batki et al., 2000 (CPDD abstract)

  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

  20. Methamphetamine Use

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

  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 Zoloft + no CM Proportion Meth Positive 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 2 week non-med baseline Baclofen 20mg tid Gabapentin 800mg tid Placebo tid Randomization 16 week medication trial Thrice Weekly Matrix Model Counseling

  28. Demographics *p < 0.05

  29. Demographics

  30. Drug Use History 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

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