Project Summary/Abstract Methamphetamine use is a major driver of drug-related morbidity and mortality, with intimate involvement in the national opioid crisis as well. Methamphetamine is more prevalent than many other drugs, including opioids, with 37 million users of methamphetamine and amphetamine worldwide and 1.4 million past-year users in the U.S. alone in 2016. The annual economic cost of methamphetamine use is estimated to be $23.4 billion in the United States. There are no FDA-approved pharmacotherapies for methamphetamine use disorder, a major gap in the field of addition medicine. Promising agents such as bupropion, extended-release naltrexone, aripiprazole, and selected amphetamine-based stimulants, have all shown mixed or negative results in phase 2 clinical trials. In contrast, in two separate phase 2 clinical trials mirtazapine has demonstrated a significant effect in increasing periods of abstinence from methamphetamine and decreasing related HIV risk behaviors among adults with methamphetamine use disorder who were born male and have sex with men. While testing this product in the general population, with larger samples sizes, and more intensive adherence interventions is demanded, the first step required by the FDA is now a drug-drug interaction study to evaluate pharmacokinetics of methamphetamine in the presence of mirtazapine, to evaluate for adverse events such as QT prolongation and serotonin syndrome, and to ensure the safety of these combinations in patients with co-morbid opioid use disorder who may be using illicit opioids or maintained on agonist therapy. We propose to conduct this Phase 1 human laboratory trial, also exploring mechanisms for the effect of mirtazapine with a battery of psychological testing, with 36 subjects (Group 1 with no opioid use, Group 2 with illicit opioid use, Group 3 with opioid use disorder maintained on methadone) in a within-subject crossover study. After screening, participants will be admitted to a 16-day inpatient stay, randomly assigned to mirtazapine or placebo, followed to steady state, and given placebo and a methamphetamine infusion with associated batteries of psychological testing; they will then be followed for 5 days for washout and initiated in the opposite treatment arm. Results will contribute toward further evaluation of mirtazapine for treatment of methamphetamine use disorder.

Project Summary/Abstract This is a phase 1 trial of the safety of mirtazapine for methamphetamine use disorder, including 3 subgroups to ensure safety among those with methamphetamine use disorder and also comorbid opioid use disorder. We will enroll a total of 36 participants in a randomized double-blind within-subject crossover design entailing 16 days of inpatient care and a follow-up visit. The inpatient visit will include a test dose of methamphetamine to ensure tolerability, achievement of steady state of mirtazapine or placebo, infusion of placebo and then methamphetamine IV challenge, washout, and institution of the opposite arm. Safety labs, a psychological battery of tests, and pharmacokinetic studies will be conducted to establish the potential impact of mirtazapine on methamphetamine pharmacokinetics with and without the presence of morphine or methadone, as well as cardiac (i.e. QTc duration) and other adverse events (e.g. serotonergic symptoms/signs). Data will help to move mirtazapine to the next stage of development for methamphetamine use disorder.