Development of Drinabant for Treatment of Acute Cannabinoid Overdose

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Acute cannabinoid overdose (ACO) results from the consumption of large quantities of cannabinoid compounds. These include delta-9-tetrahydrocannabinol (THC), the naturally occurring psychoactive compound in Cannabis plants, as well as other synthetic cannabinoid (SC) compounds. Although SCs are chemically distinct from THC, THC and SCs elicit psychoactive effects through the binding and activation of cannabinoid (CB) receptors in the brain, principally the CB-1 receptor. Initially developed as research tools to study CB receptors, SCs are reported to be more potent and efficacious than THC at activating CB-1 receptors. A critical issue with edibles is that absorption of the THC/SC through the gut is delayed compared to smoking. The subsequent delay in the onset of a high leads some to overconsume these edibles. Because it can be difficult to gauge how much THC/SC is contained in an individual edible, this overconsumption can quickly result in an overdose. Symptoms of ACO have been reported to last anywhere from several hours to days, leading some individuals to require emergency medical attention or even hospitalization. Individuals using SCs are about 30 times more likely to require emergency medical care than for smoked marijuana. The therapeutic hypothesis is that a CB-1 antagonist can reverse the clinical manifestations of ACO by replacing the agonist (THC or SC) bound to CB-1 receptors. Prior clinical studies have demonstrated that oral administration of CB-1 antagonists (drinabant, surinabant) can block the pharmacodynamic effects of inhaled THC. Orally administered drinabant has a slow onset, making it impractical to administer in the acute overdose setting. To improve the pharmacokinetics, the lead collaborators have proposed a parenteral route of administration (intravenous or intramuscular injection) that would be more amenable to treating ACO in the emergency medical setting. BrIDGs scientists have initiated a preclinical development campaign to advance drinabant to clinical evaluation. Development of an injectable formulation and dose range finding toxicology studies are underway . Planned activities include the pharmacokinetic and toxicology studies needed to support an Investigational New Drug (IND) application.