Project Summary/Abstract There is a significant unmet medical need to sequester and remove orally ingested prescription and illicit stimulants from the gastrointestinal (GI) tract, to prevent and treat overdose. The availability, use, misuse, and abuse of prescription and illicit stimulants has increased dramatically over the past decade across all ages ranging from children to adults. Over 4M children and young adults in the U.S. take prescription stimulants for treatment of attention deficit hyperactivity disorder (ADHD), and emergency room (ER) visits associated with these medications are estimated at over 200,000 annually. In 2020, 5.1 million people aged 12 and older reported the misuse of prescription stimulants in the past year and 758,000 had a prescription stimulant use disorder. The current standard of care, oral administration of charcoal, has limited efficacy. The illicit stimulant methamphetamine is the fastest growing drug of abuse in the U.S., yet no current therapeutics are available for treating meth intoxication. Similar compounds are widely used as “Club” drugs, and are potentially lethal, especially in combination with alcohol consumption. Therefore, a potent, easy-to-administer antidote is needed to rapidly bind, and prevent absorption of, orally ingested stimulants to the bloodstream. Such an immediate treatment will save lives. The goal of this project is to develop a broad-spectrum orally administered antidote to prevent and treat acute life-threatening intoxication caused by orally ingested stimulants. Our antidote is based on a novel class of sequestrants that tightly bind, inactivate, and clear harmful substances from the body with high specificity. When taken orally, they work in the GI tract and reduce absorption of targets to the blood and brain. The standard of care, charcoal, has a number of limitations. In contrast, our water-soluble sequestrants are more potent, faster-acting, safe, and easy to administer. To select a potent therapeutic, we will undertake the following Aims: Aim 1 will complete in-vitro screening for binding affinity of sequestrants against a broad spectrum of stimulants and select a candidate for in-vivo study. We will screen for binding affinity and selectivity. We will evaluate individual stimulants with and without the presence of alcohol. Expected outcome is one lead orally administered therapeutic candidate for in-vivo study. Aim 2 will evaluate the lead candidate in-vivo for both tolerability and efficacy against orally administered stimulants in a rodent model, using charcoal as control. We will quantify the efficacy and time course of the lead candidate to 1) eliminate amphetamine, methylphenidate, and 3,4-methylenedioxymethamphetamine, at concentrations sufficient to cause significant intoxication, from the gastrointestinal tract into feces, and 2) prevent absorption of these compounds into the bloodstream, via their quantification in plasma and urine. In addition, we will monitor physiological parameters and behavior. These studies will establish the dose range for this oral treatment. Expected outcome is a candidate that provides rapid clearance of stimulants from the body and reversal of physiological and behavioral signs of toxicity, ready for large animal studies.

PROJECT NARRATIVE There is a significant unmet need to treat overdose caused by orally ingested prescription and illicit stimulants. The proposed work will develop a broad-spectrum orally administered antidote to prevent and treat acute life- threatening intoxication caused by these stimulants. Such an immediate treatment will save lives.