Targeting brain inflammation to treat methamphetamine addiction

Transcription

1 Targeting brain inflammation to treat methamphetamine addiction Keith Heinzerling MD MPH UCLA Center for Behavioral and Addiction Medicine UCLA Department of Family Medicine October 23, 2014 Advancing the prevention and treatment of chronic illnesses with a focus on addiction and HIV UCLA Department of Family Medicine

2 Disclosure Information Targeting brain inflammation to treat methamphetamine addiction Keith Heinzerling, MD, MPH Continuing Medical Education committee members and those involved in the planning of this CME Event have no financial relationships to disclose. Keith Heinzerling, MD, MPH I have the following financial relationships to disclose: Consultant for: Gilead Grant/Research support from: MediciNova, Inc. (study medication), Pfizer (study medication), and National Institute on Drug Abuse -and I will discuss the following off label use and/or investigational use in my presentation: Bupropion and ibudilast: will discuss results of clinical trials testing investigational medication for methamphetamine dependence including bupropion and ibudilast

3 Methamphetamine Strong psychoactive stimulant: Release of norepinephrine/dopamine Euphoria, mood, alertness, sleep, psychosis, risky behavior (HIV), Parkinson s Disease Heart rate, blood pressure, arrhythmia, heart attack/stroke Methamphetamine (Meth) Addiction: Compulsive use, impulsivity, cravings/urges Tolerance and withdrawal ( Crash ), energy/drive, depression, concentration, sleep Poor decision making/planning/executive functioning

4 Methamphetamine-related Deaths Calcaterra S. Subst Abus. 2013;34(2):

5 Meth use is risk for HIV infection Meth use >2-4 fold increases in risk for HIV transmission in: Cohort Studies (Plankey et al., 2007) New Infections (Drumright et al., 2007; 2009) STI settings (Buchacz et al., 2005; Buchbinder et al., 2005) Meth use > increased risk of HIV sexual risk behaviors Santos GM. Dose-response associations between number and frequency of substance use and high-risk sexual behaviors among HIV-negative substance-using men who have sex with men (SUMSM) in San Francisco. J Acquir Immune Defic Syndr Aug 1;63(4):540-4.

6 Relapse is common with behavioral treatments for meth addiction Outpatient Counseling (Cognitive Behavioral Therapy): Only 33% of meth users finished 16 weeks of therapy Only 45% achieved 3 weeks of meth abstinence Hillhouse MP. Addiction Apr;102 Suppl 1: % of meth users relapsed during first year post-discharge Longer time to relapse: Serious meth-related psychological/behavioral problems Longer initial treatment Self-help participation post-discharge Shorter time to relapse: Parent with alcohol or drug problems Involvement in meth sales Brecht ML. Drug Alcohol Depend Jun 1;139:18-25.

7 Relapse is common with behavioral treatments for meth addiction (2) Inpatient Treatment: Detox : Only 20% long-term abstinent Residential: High rate of relapse post-discharge and only 30% long-term abstinent McKetin R, Addiction Nov;107(11): Meth Use 20% 30%

8 Brain circuits involved in addiction: Dopamine and glutamate Glutamate: Decision Making, Planning, Resisting Urges Meth activates dopamine Dopamine: Reward, Habit, Learning Le Foll B. CMAJ Nov 20;177(11):

9 Meth users have dysfunction in brain dopamine and glutamate systems A (B) Orbitofrontal cortex function (OFC; glutamate): Poor decision making, ability to resist urges and cravings Volkow ND, Nature Reviews Neuroscience 5, (December 2004) (A) Dopamine transporters: Ability to respond to non-drug rewards, impulsivity, favor immediate > delayed reward Volkow ND, Am J Psychiatry. 2001;158(3):

10 Meth users with worse dopamine function are more likely to relapse A A (A) Dopamine function predicts cocaine relapse (B) Dopamine transporters return by 14 months meth abstinence, but many patients relapse before then! B Martinez D, Am J Psychiatry. 2011;168(6): Volkow N D et al. J. Neurosci. 2001;21:

11 Bupropion: dopamine-norepinephrine re-uptake inhibitor for meth? Randomized trial of bupropion SR 150 mg twice daily versus placebo for 12 weeks in methamphetamine users with less than daily meth use Total sample Bupropion (N=41) Placebo (N=43) P value End of treatment abstinence 29% (12) 14% (6) Only 32% (13/41) of bupropion participants were deemed medication adherent via week 6 plasma bupropion level. Adherence was strongly associated with end of treatment meth abstinence. Bupropion only Adherent (N=13) Non-adherent (N=28) P value End of treatment abstinence 54% (7) 18% (5) Heinzerling KG. Addiction Jun 4.

12 Medications that reduce brain dysfunction may reduce meth relapse But despite numerous trials, no effective medication for meth has been identified Dopaminergic meds: bupropion, modafinil, methylphenidate, d-amphetamine Antidepressants: sertraline, mirtazapine Anticonvulsants: topirimate, gabapentin Other: baclofen, ondansetron New strategies to treat brain dysfunction in meth users and reduce relapse rates are needed

13 The brain s immune cells may be important in brain diseases The blood s immune cells The brain s immune cells

14 Resting Microglia = Neuroprotective Activated Microglia = Neurotoxic Inflammatory cytokines METH Neurotrophins Benarroch EE. Neurology Sep 17;81(12): Neurotrophins

15 Meth is toxic to the brain triggering glial activation and neuroinflammation Activated microglia in meth users Neuroinflammation persists despite years of abstinence and may trigger relapse Sekine Y. J Neurosci May 28;28(22):

16 HIV also activates microglia and meth increases HIV-related neurotoxicity Areas with activated microglia in HIV positive versus HIV negative controls Garvey L. AIDS. 28(1):67-72, January 2, Microglial activation on brain scans was associated with worse executive functioning (Garvey, 2014) Meth + HIV results in worse cognitive function than either alone (Carey, 2006) Meth use associated with retroviral non-adherence and poor treatment outcomes in HIV infection (Rajasingham, 2012)

17 Reducing brain inflammation may brain function and meth relapse Ibudilast (MN-166, MediciNova, Inc.) Inhibits phosphodiesterases and macrophage migration inhibitory factor Microglial activation and neuroprotection Inflammatory cytokines (IL-1β, IL-6, TNF-α) and neurotrophins (BDNF, GDNF) Ibudilast black holes (total myelin loss and neuron degeneration) on MRI in Multiple Sclerosis (Barkhof, 2010) From: Sahraian, 2009

18 Ibudilast shows promise in meth addiction Ibudilast reduces the number of times rats self-administer methamphetamine (Snider, 2013) Ibudilast (100 mg) improved a measure of attention in meth users 48 hours after last meth dose (Swanson, 2013): Reduced variability in response times (U=0.00, p=.02, r=-.82) and perseverative responses (U=1.50, p=.04, r=-.71) on the Conner s Continuous Performance Test-II (CPT-II)

19 Ibudilast-meth human lab study Highest dose of ibudilast (50 mg twice daily) reduced several methamphetamine subjective effects

20 UCLA conducting a Phase 2 clinical trial of ibudilast for meth dependence First study to test if ibudilast can help meth users to reduce/stop meth use 140 patients with methamphetamine dependence (70 HIV positive and 70 HIV negative) Random assignment to ibudilast 50 mg twice a day or placebo twice a day for 12 weeks Weekly counseling sessions and physician visits Extensive neurocognitive battery CD4 count, HIV RNA, ARV adherence Serum markers of inflammation (cytokines, neurotrophins, CRP, uric acid) DNA testing Funding from NIDA and MediciNova, Inc. (NCT )

21 In Conclusion The neurotoxic effects of meth activate brain microglia Resulting neuroinflammation may cause cognition and relapse rate seen in meth addiction, especially in HIV positive patients Reducing microglial activation may cognitive function and meth relapse rates Ibudilast may be an effective treatment for meth Ibudilast reduces microglial activation Resulting neuroinflammation and neuroprotection may cognitive function and meth relapse rates, especially in HIV positive pts

22 THANK YOU! If you d like to learn more about meth research or treatment at UCLA CBAM: Call UCLA Visit Follow us on Twitter (@UCLACBAM) and Facebook ( kheinzerling@mednet.ucla.edu or cbam@mednet.ucla.edu Advancing the prevention and treatment of chronic illnesses with a focus on addiction and HIV UCLA Department of Family Medicine