Advancing Troriluzole as a Treatment for Methamphetamine Use Disorder: A Human Laboratory Study - ABSTRACT Methamphetamine use disorder (MUD) presents a serious public health problem in the United States of America. Overdose death rates from methamphetamine have also risen considerably, which has been caused by both methamphetamine use alone AND co-use of methamphetamine and opioids. Similarly, although problems posed by MUD are attributable largely to use of methamphetamine, MUD is often co-morbid with opioid use disorder (OUD), making MUD even more difficult to treat. Novel pharmacotherapeutic strategies need to be evaluated and advanced to better treat MUD alone, as well as co-morbid MUD and OUD. Glutamate systems play an essential role in the direct reinforcing effects of methamphetamine and methamphetamine-induced reinstatement of drug seeking. Previous research has also demonstrated methamphetamine produces persistent disruptions in brain glutamate systems (i.e., disrupted glutamate homeostasis). A growing body of literature, largely preclinical, indicates targeting disrupted glutamate homeostasis is a promising strategy for reducing methamphetamine intake and mitigating other abuse-related effects of methamphetamine. Troriluzole, a third-generation prodrug of riluzole, reduced methamphetamine intake and seeking behaviors in self-administration assays, inhibited development, expression and maintenance of methamphetamine conditioned place preference and ameliorated methamphetamine-induced changes in glutamate neurochemistry. The overarching goal of this study is to translate preclinical findings with troriluzole into the human laboratory to advance troriluzole as an MUD pharmacotherapy. We seek to extend that work by evaluating troriluzole in people with MUD alone and co-morbid MUD and OUD given the epidemiological findings described above and the key role of glutamate in opioid addiction. To this end, 40 non-treatment seeking human subjects meeting diagnostic criteria for MUD (20 with MUD alone and 20 with co-morbid MUD and OUD; 50% men and 50% women in each group) will be enrolled in a placebo-controlled, double-blind, randomized human laboratory experiment in which we will assess the reinforcing effects of intravenous methamphetamine (0, 15 and 30 mg) following treatment with troriluzole (0, 140 and 280 mg/day). Validated and widely used subjective drug-effect, physiological and side effects measures will also be used. The research proposed here will directly translate findings from preclinical research and provide the initial clinical evidence that troriluzole reduces the reinforcing and other abuse-related effects of methamphetamine. This study will also provide basic science information about the glutamatergic mechanisms underlying the pharmacodynamic effects of methamphetamine in humans. As such, the outcomes will advance our understanding of the clinical neurobiology of MUD alone and co-morbid MUD and OUD.
