Synthetic cannabinoids (i.e., “Spice”, “K2”) are emerging drugs of abuse that are associated with a host of adverse effects and visits to hospital emergency departments. In contrast to phytochemical cannabinoids derived from the cannabis plant (e.g., THC), less is known about the mechanisms responsible for their behavioral and physiological effects. Dr. William Fantegrossi, Associate Professor of Pharmacology and Toxicology at the University of Arkansas for Medical Sciences, uses rodent models to examine the neuropharmacological mechanisms contributing to their adverse effects. In a recent study (http://jpet.aspetjournals.org/content/early/2018/11/21/jpet.118.251157), Dr. Fantegrossi and his graduate student, Catheryn Wilson, examined the convulsant effects of two chemically dissimilar synthetic cannabinoids in mice. Seizures and convulsions are two of the most severe adverse effects associated with the use of synthetic cannabinoids in humans, but the mechanisms responsible for these effects are not fully understood, and potential treatments to reverse these effects have not been tested. Dr. Fantegrossi’s research team treated mice with the synthetic cannabinoid full agonists, JWH-018 and 5F-AB-PINACA, the phytochemical partial cannabinoid agonist, THC, and the non-cannabinoid chemical convulsant, pentylenetetrazol (PTZ). The two synthetic cannabinoids and PTZ reliably induced convulsant activity in a dose-dependent manner, whereas THC did not. Repeated administration of THC and JWH-018 produced tolerance to the convulsant activity of JWH-018 and 5F-AB-PINACA, but cross tolerance was not conferred to PTZ. Repeated administration of PTZ increased sensitivity to its convulsant effects, but did not alter the convulsant effects of synthetic cannabinoids. Importantly, the convulsant effects of synthetic cannabinoids were fully blocked by THC and the cannabinoid (CB1) receptor antagonist, rimonabant, but not by the prototypical anticonvulsant, diazepam. These findings indicate that that convulsant effects of two chemically dissimilar synthetic cannabinoids are both mediated by their strong agonist activity at CB1 receptors. The most clinically relevant finding of this study is that diazepam did not block the convulsant effects of either synthetic cannabinoid, even at a dose that completely blocked the convulsant effects of PTZ. Clinical reports of seizures and convulsions following the use of synthetic cannabinoids in humans usually report administration of diazepam and other benzodiazepines to medically manage these adverse effects. The findings obtained by Dr. Fantegrossi and his colleagues suggest that benzodiazepines may not be an effective treatment for these individuals, and suggest that acute administration of a CB1 antagonist like rimonabant might be a better therapeutic option. We know that cannabinoid-induced convulsions are consistent across species, given case reports of convulsions in domestic dogs and their owners following accidental or intentional ingestion of commercial Spice preparations. The animal model developed by Dr. Fantegrossi and his colleagues closely mimics the convulsant activity observed in human users. Cannabinoid-induced convulsions are typically witnessed by family or friends of the user at the time of use. Given the short duration of action of most synthetic cannabinoids, EEG readings (which are necessary to determine the presence of seizures) have typically returned to normal by the time the user arrives at the emergency department. Dr. Fantegrossi is currently conducting studies to measure the contributing role of seizures in eliciting cannabinoid-induced convulsant activity, which will represent a significant step forward in understanding the neurobiological mechanisms responsible for these effects. Dr. Fantegrossi has been a member of CPDD since 2001. He has previously served on the Electronics Committee, the Drug Evaluation Committee (2000-2006), and the Program Committee (2012-2014). He currently serves on the Committee for Abuse Liability Testing. Dr. Smith has been a member of CPDD since 1994. He currently serves on the Board of Directors and as Chair of the Animals in Research Committee. He previously served as Chair of the Awards Committee (2013-2017). By Mark Smith, Ph.D., Animals in Research Committee Chair.
