The K2/Spice phenomenon: emergence, identification, legislation and metabolic characterization of synthetic cannabinoids in herbal incense products

Abstract

In 2008, the European Monitoring Center for Drugs and Drug Addiction (EMCDDA) detected unregulated, psychoactive synthetic cannabinoids (SCBs) in purportedly all-natural herbal incense products (often known as K2 or Spice) that were being covertly abused as marijuana substitutes. These drugs, which include JWH-018, JWH-073 and CP-47,497, bind and activate the cannabinoid receptors CB1R and CB2R with remarkable potency and efficacy. Serious adverse effects that often require medical attention, including severe cardiovascular, gastrointestinal and psychiatric sequelae, are highly prevalent with SCB abuse. Consequently, progressively restrictive legislation in the US and Europe has banned the distribution, sale and use of prevalent SCBs, initiating cycles in which herbal incense manufacturers replace banned SCBs with newer unregulated SCBs. The contents of the numerous, diverse herbal incense products was unknown when SCB abuse first emerged. Furthermore, the pharmacology of the active components was largely uncharacterized, and confirmation of SCB use was hindered by a lack of known biomarkers. These knowledge gaps prompted scientists across multiple disciplines to rapidly (1) monitor, identify and quantify with chromatography/mass spectrometry the ever-changing contents of herbal incense products, (2) determine the metabolic pathways and major urinary metabolites of several commonly abused SCBs and (3) identify active metabolites that possibly contribute to the severe adverse effect profile of SCBs. This review comprehensively describes the emergence of SCB abuse and provides a historical account of the major case reports, legal decisions and scientific discoveries of the "K2/Spice Phenomenon". Hypotheses concerning potential mechanisms SCB adverse effects are proposed in this review.

Figure 1

Representations of SCB-laced herbal incense commonly called K2 (A), typical packaging of K2 and similar products (B), and labeling of K2 packages that explicitly states “not for consumption” (C). Figures (A) and (B) are courtesy of the DEA. Figure (C) is courtesy of the Arkansas Department of Health, Public Health Laboratory.

Figure 2

The psychoactive constituent of marijuana, Δ⁹-THC, is depicted here with the first generation of SCBs commonly found in K2 products. The five SCBs shown were the first to be controlled by the US Federal Government after the emergence of K2 products.

Figure 3

Levels of pharmacological efficacy exhibited by drugs acting at G-protein coupled receptors.

Figure 4

Agonism of CB1R activates the G_i/o protein, which inhibits adenylyl cyclase activity, lowering intracellular cyclic AMP concentrations.

Figure 5

Major JWH-018 metabolites as determined by in vitro metabolism studies (A) and urinalysis after confirmed JWH-018 use (B).