Rescue from Synthetic Cannabinoid Intoxication

Abstract

The number of patients seeking emergency treatment for acute synthetic cannabinoid intoxication have increased over the past decade, despite laws prohibiting their legal sale and use. Reported clinical signs of acute synthetic cannabinoid intoxication include tachycardia and hypertension, lethargy, confusion, agitation, hallucinations, and seizures. Clinicians have little guidance on the best course of treatment for such patients. The current standard of care involves administering benzodiazepines to sedate agitated patients and reverse seizures, antidepressants to treat anxiety reported by patients, and antipsychotics to reverse apparent psychotomimetic effects. However, the effectiveness of these treatments remains unclear. Here, in adult male C57 mice, the ability of several clinically available medications to reverse effects including hypothermia, antinociception, and ataxia of the synthetic cannabinoid JWH‐018 are examined. Additionally, effects of JWH‐018 on blood pressure and heart rate are determined, to evaluate potential cardiac effects. JWH‐018 (0.3, 1.0, or 3.0 mg/kg) or vehicle was administered 10‐min prior to test agents which included diazepam (1 & 10 mg/kg), imipramine (10 & 30 mg/kg), fluvoxamine (10 & 30 mg/kg), and haloperidol (0.3 & 3 mg/kg). Effects of these agents are compared to those of rimonabant (1 & 3 mg/kg), the CB1 antagonist. Behavioral effects were assessed immediately before, then 10, 20, 30, 40, and 50‐min after JWH‐018 administration. In other mice, cardiac effects were assessed 25–35 min after JWH‐018 administration. The potential reversal agents are administered after JWH‐018 administration because the clinical situation necessitates administration of reversal agents after cannabinoid exposure. JWH‐018 had no effect on blood pressure and only modestly decreased heart rate. As expected, JWH‐018 had dose‐dependent effects on rectal temperature, antinociception, and ataxia that persisted for at least 50‐min. Within 10–20 min of administration, rimonabant reversed hypothermic and antinociceptive effects and partially reversed ataxic effects of JWH‐018. No other agent tested affected any of the JWH‐018 effects. These results suggest that clinical reports of hypertension and tachycardia are unlikely to be due to direct effects of synthetic cannabinoids, but rather are likely due to the situation arising from intoxication requiring emergency medical care. Further, while treatment with a sedative might help calm an agitated patient, these medications are unlikely to alter the course of synthetic cannabinoid intoxication. Finally, although rimonabant was withdrawn from human use, this decision was based on adverse events during chronic rimonabant treatment for obesity. These results indicate that rimonabant or a similar drug could be useful for acute reversal of synthetic cannabinoid intoxication.Support or Funding InformationSupported by The Department of Defense (JPC‐5) project FA8650‐15‐C‐6589