Varenicline vs Placebo for the Treatment of Methamphetamine Dependence

Overview

Methamphetamine (MA) abuse is the fastest growing drug problem in the United States and is responsible for significant public health complications, including HIV infection. As a result effective treatments for MA dependence are urgently needed. There are currently no efficacious medications for MA dependence, although results from preliminary randomized trials of bupropion for MA dependence found bupropion to be more effective than placebo, but only among subgroups of participants, including those with lower frequency of MA use at baseline. A growing body of preclinical and clinical studies suggest that cholinergic mechanisms play an important role in the neurobiology of MA and other stimulant dependence, such as nicotine dependence. Mechanistically, cholinergic medications may alleviate MA-associated cognitive dysfunction, thereby improving outcomes of treatment for MA dependence. Varenicline is a partial agonist at α4β2 nicotinic receptors and a full agonist at α7 nicotinic receptors that has been approved as an anti-cigarette smoking medication. In order to assess the potential efficacy of varenicline for methamphetamine dependence, we will perform a clinical trial to assess if varenicline compared to placebo results in greater: 1. reductions in methamphetamine use; 2. treatment retention;

Methamphetamine (MA) abuse is the fastest growing drug problem in the United States and is responsible for significant public health complications, including HIV infection1. As a result effective treatments for MA dependence are urgently needed. There are currently no efficacious medications for MA dependence, although results from preliminary randomized trials of bupropion for MA dependence found bupropion to be more effective than placebo, but only among subgroups of participants, including those with lower frequency of MA use at baseline 2, 3. A growing body of preclinical and clinical studies suggest that cholinergic mechanisms play an important role in the neurobiology of MA and other stimulant dependence, such as nicotine dependence 4. Mechanistically, cholinergic medications may alleviate MA-associated cognitive dysfunction, thereby improving outcomes of treatment for MA dependence 5. Varenicline is a partial agonist at α4β2 nicotinic receptors and a full agonist at α7 nicotinic receptors that has been approved as an anti-cigarette smoking medication. In order to assess the potential efficacy of varenicline for methamphetamine dependence, we will perform a clinical trial to assess the following aims: 1. To determine if varenicline results in significantly greater reductions in methamphetamine use than placebo, as determined via the proportion of methamphetamine-free urine specimens provided by participants throughout treatment, when provided to methamphetamine dependent participants in conjunction with cognitive behavioral therapy. Exploratory Aim 1a. To determine whether reductions in methamphetamine use with varenicline versus placebo are greater among methamphetamine dependent participants with baseline light MA use (MA use on 18 or fewer of the past 30 days at baseline) versus heavy MA use (MA use on more than 18 of the past 30 days). Exploratory Aim 1b. To determine if varenicline results in a greater proportion of methamphetamine dependent participants achieving methamphetamine abstinence defined as self-reported MA abstinence, confirmed via urine drug screens (all available urine drug screens are MA-metabolite free and at least one urine drug screen available per week and no more than two missed visits between urine drug screens) during the final two weeks of the study medication period (weeks 7 and 8) relative to placebo when provided in conjunction with cognitive behavioral therapy. 2. To determine if varenicline results in significantly greater treatment retention than placebo among MA dependent participants when provided in conjunction with cognitive behavioral therapy. To address these aims, we recruited 20 MA dependent participants who will be randomized to receive treatment with varenicline (n=10) or placebo (n=10) for 8 weeks, in combination with cognitive behavioral therapy, followed by 4 weeks of follow up observation. Results of this study have the potential to provide additional safety data and to yield preliminary evidence that may support a fully powered late Phase II trial of the efficacy of varenicline for the treatment of methamphetamine dependence. Findings also have potential to provide insights into the influence of cognitive dysfunction, and medications with potential cognitive enhancing effects, on the pathogenesis of MA dependence and treatment outcomes.