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

Life Sci. 2014 Feb 27;97(1):45-54. doi: 10.1016/j.lfs.2013.09.017. Epub 2013 Sep 29.

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Cannabinoid Receptor Agonists / metabolism
  • Cannabinoid Receptor Agonists / pharmacology
  • Cannabinoid Receptor Agonists / toxicity
  • Cannabinoids / metabolism
  • Cannabinoids / pharmacology*
  • Cannabinoids / toxicity
  • Designer Drugs / metabolism
  • Designer Drugs / pharmacology*
  • Designer Drugs / toxicity
  • Dronabinol / metabolism
  • Dronabinol / pharmacology*
  • Dronabinol / toxicity
  • Humans
  • Illicit Drugs / metabolism
  • Illicit Drugs / pharmacology
  • Illicit Drugs / toxicity
  • Receptor, Cannabinoid, CB1 / agonists
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptor, Cannabinoid, CB2 / agonists
  • Receptor, Cannabinoid, CB2 / metabolism

Substances

  • Cannabinoid Receptor Agonists
  • Cannabinoids
  • Designer Drugs
  • Illicit Drugs
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • Dronabinol