Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to Δ(9)-THC: mechanism underlying greater toxicity?

Abstract

K2 or Spice products are emerging drugs of abuse that contain synthetic cannabinoids (SCBs). Although assumed by many teens and first time drug users to be a "safe" and "legal" alternative to marijuana, many recent reports indicate that SCBs present in K2 produce toxicity not associated with the primary psychoactive component of marijuana, ∆(9)-tetrahydrocannabinol (Δ(9)-THC). This mini-review will summarize recent evidence that use of K2 products poses greater health risks relative to marijuana, and suggest that distinct pharmacological properties and metabolism of SCBs relative to Δ(9)-THC may contribute to the observed toxicity. Studies reviewed will indicate that in contrast to partial agonist properties of Δ(9)-THC typically observed in vitro, SCBs in K2 products act as full cannabinoid receptor type 1 (CB1R) and type 2 (CB2R) agonists in both cellular assays and animal studies. Furthermore, unlike Δ(9)-THC metabolism, several SCB metabolites retain high affinity for, and exhibit a range of intrinsic activities at, CB1 and CB2Rs. Finally, several reports indicate that although quasi-legal SCBs initially evaded detection and legal consequences, these presumed "advantages" have been limited by new legislation and development of product and human testing capabilities. Collectively, evidence reported in this mini-review suggests that K2 products are neither safe nor legal alternatives to marijuana. Instead, enhanced toxicity of K2 products relative to marijuana, perhaps resulting from the combined actions of a complex mixture of different SCBs present and their active metabolites that retain high affinity for CB1 and CB2Rs, highlights the inherent danger that may accompany use of these substances.

Keywords: CB1 receptors; CB2 receptors; Drug abuse; Drug metabolism; K2/Spice; Synthetic cannabis; ∆(9)-Tetrahydrocannabinol.

Figure 1. Structures of representative SCBs commonly found in K2 products

Synthetic cannabinoids are derived from diverse structural groups, including classical cannabinoids (Δ⁹-THC), cyclohexylphenols (CP-47,497), naphthoylindoles (JWH-018), naphthylmethylindoles (JWH-175), naphthylmethylindenes (JWH-176), benzoylindoles (RCS-4), phenylacetylindoles (JWH-250), adamantoylindoles (AKB48), and tetramethylcyclopropylindoles (UR-144).

Figure 2. Comparison of the in vivo and in vitro efficacy for SCBs and Δ⁹-THC

Panel A: CP-55,940, JWH-073 and the M1-metabolite of JWH-073 activate G-proteins with greater efficacy than Δ⁹-THC. Originally published in PLoS One, 6:e21917, 2011 (Brents et al., 2011). Copyright permission granted by PLoS One open access license. Panel B: CP-55,940, JWH-018 and the M1-metabolite of JWH-018 activate G-proteins more potently and efficaciously than Δ⁹-THC. Originally published in Biochemical Pharmacology, 83:952, 2012 (Brents et al., 2012). Copyright permission granted by Elsevier. Panel C: JWH-018 and the M1-metabolite of JWH-018 produce greater levels of hypothermia than Δ⁹-THC. Originally published in Biochemical Pharmacology, 83:952, 2012 (Brents et al., 2012). Copyright permission granted by Elsevier.

Figure 3. In vivo and in vitro interactions between JWH-018 and JWH-073

Co- administration of JWH-018 and JWH-073 results in synergistic interactions for Δ⁹-THC drug discrimination (Panel A), analgesia (Panel B) and displacement of radioligand from CB1 receptors (Panel C). Data presented in all panels were originally published in the Journal of Pharmacology and Experimental Therapeutics, 346:350, 2012 (Brents et al., 2013). Copyright permission granted by ASPET.

Figure 4. Summary of known metabolism, excretion and downstream cellular signaling activity of JWH-018 and AM2201, two popular SCBs found in K2 products

“+” indicates agonism, “−” indicates antagonism, “X” indicates no binding affinity, “?” indicates not known.