Evaluation of CB1 antagonists as antidotes for synthetic cannabinoid toxicity in male and female mice

Abstract

While a plethora of recreational marijuana and cannabis derived products have been legalized across the United States, recent trends also indicate an increase in the number of emergency calls relating to the overdose or accidental exposure to Δ9‐tetrahydrocannabinol (THC) and/or synthetic psychoactive cannabinoids. There are currently no FDA approved medications for treating acute cannabinoid toxicity. To address this public health issue, here we provide key data towards the discovery and development of an effective antidote for treating acute toxicity symptoms that may be associated with cannabis overdose, and by ingestion of certain cannabimimetics such as the potent CB1 receptor agonist JWH‐018. Previously, we established proof‐of‐concept and presented preliminary data showing that the novel CB1 antagonist AM11503 (10 mg/kg, i.v.) effectively reversed the hypothermic effects of an acute dose of JWH‐018 (6 mg/kg, i.p.), effects that were similar to the known CB1 antagonist rimonabant (10 mg/kg, i.v.). Herein, we extend this line of research in male and female CD‐1 mice by: a) examining whether AM11503 induces rimonabant‐like effects on observable behavior; b) assessing the ability of AM11503 to prevent JWH‐018‐mediated tremors and convulsions; and c) comparing the ability of AM11503 and rimonabant to precipitate somatic signs of withdrawal in JWH‐018‐dependent mice. Results show that rimonabant (3.2–32 mg/kg, i.v.) produced a dose‐related increase in scratching and grooming in both male and female mice compared to controls, whereas AM11503 (3.2–32 mg/kg, i.v.) did not alter stereotypic behavior. In interaction studies, administration of 10 mg/kg (i.v.) AM11503 fully blocked tremors and convulsions induced by “suprapharmacological” doses of JWH‐018 (18 mg/kg, i.p.). Finally, rimonabant (10 mg/kg, i.v.) induced significant somatic signs of withdrawal, i.e., head twitches and paw tremors, in male and female mice that were repeatedly exposed to JWH‐018 (3 mg/kg, i.p. once per day for 6 days) compared to vehicle‐treated subjects. In contrast, AM11503 (10 mg/kg, i.v.) did not induce somatic signs of withdrawal in JWH‐018‐dependent mice and effects were similar to vehicle‐treated mice. In conjunction, the inability of AM11503 to produce rimonabant‐like stereotypic behaviors and precipitate somatic signs of withdrawal yet prevent CB1 agonist‐induced acute toxicity allows for the identification and development of safer CB1 antagonist‐based therapies for nullifying synthetic cannabinoid toxicity.Support or Funding InformationFunding Information: Work supported by NIDA/NIH grants R21DA045882 and R41DA044048