Synthetic Cannabinoids: Rapidly Emerging Drugs of Abuse

Abstract

K2, also called “Spice” or “synthetic marijuana,” is a rapidly emerging drug of abuse that possesses psychoactive properties similar to those of Δ9‐tetrahydrocannabinol (Δ9‐THC). K2 use has exploded in many sections of the population including teenagers and first time drug users. Use of K2 can result in extreme agitation, hallucinations, supraventricular tachycardia, syncope, and seizures. The presence of more than 20 different K2‐aminoalkyl indoles (AAIs) have been reported in various K2s, but the two most commonly observed are JWH‐018 and JWH‐073; however, new generations of structurally related compounds are constantly being produced. Our studies demonstrate for the first time that the native K2s undergoes extensive metabolism by cytochrome P450s and UDP glucuronosyltransferases. Due to the activity of these enzymes, a variety of hydroxylated metabolites, have been biosythesized and excreted in human urine primarly as glucuronidated conjugates. These metabolites were identified and characterized using LC‐MS/MS and HPLC‐UV/Vis, and steady state kinetic analyses were also investigated. Consequently, we hypothesize that the severe effects observed for some K2 users could be related to a defect in their metabolism. We have also shown that these K2 products cause psychoactive effects similar to those of Δ9‐THC by activating cannabinoid receptors (CBRs) in the central nervous system. Moreover, CBRs were able to bind several hydroxylated and glucuronidated K2‐AAI metabolites with an affinity similar to that of the parent compound. The new generation of K2s like AB‐Pinaca exhibit higher affinity, potency, and efficacy at CBRs relative to THC. Furthermore, phase one metabolites of AB‐Pinaca retain affinity and full agonist activity at CBRs. Chronic treatment of cells with AB‐Pinaca produces greater desensitization of CBRs (e.g., tolerance) than similar exposure to THC. The higher affinity and activity of AB‐Pinaca at CBRs relative to THC might be expected to produce enhanced psychotropic and adverse effects, contributing to the reported abuse and marked toxicity of this novel SCB. Finally, our in vivo data demonstrates that K2 metabolites retain biological activity in mice. Therefore, we postulate that synthetic cannabinoids and their derivatives could act as ligands for CBRs. The fact that some hydroxylated derivatives and their glucuronides can retain their biological activity makes the study of these compounds essential for understanding their severe toxicity and pharmacokinetics/dynamics.Support or Funding Information[DoD‐W81XWH1110795, NIH/NIDA DA039143 to ARP, PLP, WF and JM]