An oral therapeutic to treat intoxication by prescription and illicit stimulants

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.