Summary/Abstract The Centers for Disease Control and Prevention (CDC) reports that annually in the US, >47,000 people die of opioid overdoses, ~2 million suffer from opioid use disorder (OUD), and the annual economic burden of prescription opioid misuse is nearly $80 billion. These grim statistics are projected to worsen over the next few years as access to unprescribed opioids increases. Repetitive use of opioids can result in a dependence state and the emergence of highly aversive withdrawal symptoms when blood opioid levels wane. Individuals with OUD take unprescribed opioids chronically to avoid the emergence of withdrawal symptoms, including very high proportions of those already being treated for OUD. Unprescribed opioid use in treatment populations often leads to treatment discontinuation, which is associated with increased morbidity and mortality. Management of opioid withdrawal symptoms recently was characterized as being a “gateway to opioid dependence treatment”. Opioids induce two pathophysiological effects, excess inflammation and oxidative stress, both of which upregulate sympathetic nervous system activity and increase withdrawal system sensitivity and severity. We hypothesize that inhibiting opioid-induced inflammation and oxidative stress will blunt withdrawal symptoms. In this U18 cooperative research program, we propose to screen dimethyl fumarate (DMF), a potent anti-inflammatory and anti-oxidant agent, to determine whether it attenuates opioid withdrawal symptoms in morphine-dependent mice. DMF is the active ingredient in Tecfidera (Biogen), an FDA-approved treatment for relapsing multiple sclerosis. Should we find that DMF reduces opioid withdrawal symptoms, our data would support more comprehensive studies to fully characterize mechanisms underlying DMF’s effects. We also propose to test whether in vivo proton magnetic resonance spectroscopy (MRS) quantification of glutathione (GSH), a small peptide that plays key protective roles against inflammation and oxidative stress, detects morphine-induced GSH declines and DMF-induced GSH increases. Developing a non-invasive in vivo biomarker of opioid and DMF effects such as GSH quantification with MRS would enable longitudinal target-engagement studies of opioids’ effects in animals and, because MRS can be used in humans, would enable target-engagement studies in humans. Thus, MRS could help accelerate OUD treatment development. This program is designed to quickly lead to a go/no-go decision as to whether DMF should be further studied or developed and it addresses multiple goals of the U18 program and of the NIH HEAL initiative. The commercial viability of this approach seems high as our studies could lead to repurposing of Tecfidera or similar agents (e.g., Vumerity, Alkermes, licensed to Biogen) as an adjunct OUD treatment that reduces withdrawal symptoms and relapse vulnerability.