New Synthetic Cannabinoids Metabolism and Strategies to Best Identify Optimal Marker Metabolites

Abstract

Synthetic cannabinoids (SCs) were initially developed as pharmacological tools to probe the endocannabinoid system and as novel pharmacotherapies, but are now highly abused. This is a serious public health and social problem throughout the world and it is highly challenging to identify which SC was consumed by the drug abusers, a necessary step to tie adverse health effects to the new drug's toxicity. Two intrinsic properties complicate SC identification, their often rapid and extensive metabolism, and their generally high potency relative to the natural psychoactive Δ 9 -tetrahydrocannabinol in cannabis. Additional challenges are the lack of reference standards for the major urinary metabolites needed for forensic verification, and the sometimes differing illicit and licit status and, in some cases, identical metabolites produced by closely related SC pairs, i.e., JWH-018/AM-2201, THJ-018/THJ-2201, and BB-22/MDMB-CHMICA/ADB-CHMICA. We review current SC prevalence, establish the necessity for SC metabolism investigation and contrast the advantages and disadvantages of multiple metabolic approaches. The human hepatocyte incubation model for determining a new SC's metabolism is highly recommended after comparison to human liver microsomes incubation, in silico prediction, rat in vivo , zebrafish, and fungus Cunninghamella elegans models. We evaluate SC metabolic patterns, and devise a practical strategy to select optimal urinary marker metabolites for SCs. New SCs are incubated first with human hepatocytes and major metabolites are then identified by high-resolution mass spectrometry. Although initially difficult to obtain, authentic human urine samples following the specified SC exposure are hydrolyzed and analyzed by high-resolution mass spectrometry to verify identified major metabolites. Since some SCs produce the same major urinary metabolites, documentation of the specific SC consumed may require identification of the SC parent itself in either blood or oral fluid. An encouraging trend is the recent reduction in the number of new SC introduced per year. With global collaboration and communication, we can improve education of the public about the toxicity of new SC and our response to their introduction.

Adding more “spice” to the pot: A review of the chemistry and pharmacology of newly emerging heterocyclic synthetic cannabinoid receptor agonists

“…Oxidative metabolism of the heterocyclic scaffold of 5F‐AB‐P7AICA ( 27 ) has not been detected in in vitro (pooled human liver microsome [pHLM] assay) or in vivo (human urine) samples. Although phase I metabolites occurring via oxidation of the heterocyclic core structure of indole and indazole SCRAs are well documented in the literature, 7‐azaindole SCRAs, 19 , 25 , and 27 , may not be subject to such oxidative metabolic processes of their heterocyclic cores . Furthermore, 7‐azaindole SCRA 27 remained unchanged and often presented as the most abundant signal upon LC–MS analysis of both aforementioned in vitro and in vivo samples .…”

Metabolism of MMB022 and identification of dihydrodiol formation in vitro using synthesized standards

“…MMB022, having an in vitro half-life of 2.1 min, was classified as a high clearance compound according to McNaney et al 22 This is in line with the fact that synthetic cannabinoids are extensively metabolized 3 and consistent with the half-life previously determined for other synthetic cannabinoids. 23,24 T A B L E 2 Further formation of MMB022 metabolites by incubation of synthesized metabolites, which are in bold (IM2 epoxide, M8 dihydrodiol, M15 ester hydrolysis, IM1 ester hydrolysis + epoxide, and M5 ester hydrolysis + dihydrodiol) 10-minute metabolic stability incubation, a considerably smaller peak area was observed for M5 in comparison with M8 and M15 ( Figure 6).…”

Cannabinoids in the Pathophysiology of Skin Inflammation

“…By origin, cannabinoids may be classified either as phyto-, endo-, or synthetic cannabinoids. While only two substances, arachidonoyl ethanolamide (anandamide or AEA) and 2-arachidonoyl glycerol (2-AG), are considered primary endocannabinoids, phytocannabinoids count more than 110 members spanning 11 chemical classes, including psychotropic ∆ 9 -tetrahydrocannabinol (THC), while synthetic cannabinoids include hundreds of members divided into 6 classes [30][31][32][33]. The chemical formulas of the most relevant compounds cited in this paper are presented in Figure 1.…”

“…Synthetic cannabinoids are usually stronger CB1 and/or CB2 agonists, and due to their large and increasing number of members, they use a multitude of pathways for metabolization, depending on their chemical structure, such as oxidation, hydroxylation, oxidative defluorination, and ester hydrolysis [31].…”