Antidotes for Acute Cannabinoid Intoxication

Abstract

The cannabis constituent Δ9‐tetrahydrocannabinol (THC), now being legalized for recreational and medical use, exerts its psychotropic effects (marijuana “high”) via CB1 receptor activation. Synthetic psychoactive cannabinoids (SPCs) such as JWH‐018, illegally sold as “designer drugs”, mimic the effects of THC, a CB1 partial agonist, with higher potency, acting via CB1 receptors. Although acute toxicity is benign for consuming high doses of THC, patients admitted to the ER may exhibit symptoms of hyperemesis, irritation of conjunctival and bronchial tissue, along with impaired cognition and motor skills. SPCs act as full CB1R agonists wherein clinical manifestations associated with their consumption include, neurotoxicity represented by several negative behavioral outcomes, and even death. While such adverse events may differ among patients, current adjunctive treatments include intubation, use of benzodiazepines, antipsychotics, antihistamines, adenosine, and hypnotics, along with i.v. saline, and supportive care. Currently, there are no effective treatments available for directly blocking and reversing the effects of cannabinoid poisoning. To address this critical public‐health issue, we have initiated a drug discovery program to develop antidotes that can counteract the intoxicating/adverse effects of CB1 activation and be therapeutically useful in an emergency setting. Although CB1 antagonists such as rimonabant appear to be promising pharmacotherapeutics, this class of drugs are known to produce nausea and unacceptable pro‐depressant effects. We have now discovered a novel class of potent, selective and brain penetrant CB1 antagonists, displaying better safety profiles as compared to rimonabant. In male CD‐1 mice, these novel CB1 antagonists represented by AM11503 (10 mg/kg, i.v), antagonized the hypothermic effect induced by THC (30 mg/kg, i.p.) and was equipotent to rimonabant (10 mg/kg, i.v.) in rapidly normalizing (≤ 60 min, post‐antagonist) the hypothermia induced by an acute dose of JWH‐018 (6 mg/kg, i.p). To mimic an ER‐like situation, antagonists were given i.v., 60 min post‐ JWH‐018, where the agonist effect is at its maximum. AM11503 (10 mg/kg, i.v or 18 mg/kg, i.p) displayed no side‐effects when compared to rimonabant and AM251, which, at similar doses, induced significant stereotypic behavior (pruritic responses). Remarkably, when tested for their ability to block the neurotoxic effects of SPCs, AM11503 (10 mg/kg, i.v.) fully blocked tremors and convulsions induced by “suprapharmacological” doses of JWH‐018 (18 mg/kg, i.p). Lead optimization efforts along with safety and efficacy studies are further underway. Here, we established proof‐of‐concept and present preliminary data towards developing the first specific antidote for cannabinoid intoxication.Support or Funding InformationSupported by NIDA/NIH grant DA045882 (to KV)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.