Potential Mechanisms Underlying the Deleterious Effects of Synthetic Cannabinoids Found in Spice/K2 Products

Abstract

The chief psychoactive constituent of many bioactive phytocannabinoids (Δ9-tetrahydrocannabinol, Δ9-THC) found in hemp, cannabis or marijuana plants are scientifically denoted by the Latin term, Cannabis sativa, acts on cell surface receptors. These receptors are ubiquitously expressed. To date, two cannabinoid receptors have been cloned and characterized. Cannabinoid receptor type 1 (CB1R) is found to serve as the archetype for cannabinoid action in the brain. They have attracted wide interest as the mediator of all psychoactive properties of exogenous and endogenous cannabinoids and they are abundantly expressed on most inhibitory and excitatory neurons. Recent evidence established that cannabinoid receptor type 2 (CB2R) is also expressed in the neurons at both presynaptic and postsynaptic terminals and are involved in neuropsychiatric effects. Distinct types of cells in many regions in the brain express CB2Rs and the cellular origin of CB2Rs that induce specific behavioral effects are emerging. To mimic the bliss effects of marijuana, synthetic cannabinoids (SCBs) have been sprayed onto plant material, and this plant material has been consequently packaged and sold under brand name “Spice” or “K2”. These SCBs have been shown to maintain their affinity and functional activity for CB1R and CB2R and have been shown to cause severe harmful effects when compared to the effects of Δ9-THC. The present review discusses the potential brain mechanisms that are involved in the deleterious effects of SCBs.

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

“…79 Subsequently, azaindole 19 was found in herbal blends in Germany in 2016 80 and 2017. 81 Following the discovery of a clandestine SCRA manufacturing facility in the Hubei Province of China, NNL-1 (20) was identified and reported in 2016. 82 pyridine) nucleus.…”

“…Since 2008, multiple cases of morbidity and mortality, which are not typically observed following the consumption of cannabis, have been associated with the recreational use of products containing indole and/or indazole SCRAs. For example, over the course of one week in July 2017, approximately 158 people in Lancaster County, Pennsylvania, United States, presenting with varying symptoms ranging from hypotension to unconsciousness, were treated for SCRA‐related overdose .…”

“…15 Importantly, the growing use of SCRAs among vulnerable and marginalized population groups, including homeless and incarcerated individuals, is a growing cause for concern and has been highlighted in recent literature. [16][17][18][19] Since 2008, multiple cases of morbidity and mortality, which are not typically observed following the consumption of cannabis, 20,21 have been associated with the recreational use of products containing indole and/or indazole SCRAs. For example, over the course of one week in July 2017, approximately 158 people in Lancaster County, Pennsylvania, United States, presenting with varying symptoms ranging from hypotension to unconsciousness, were treated for SCRArelated overdose.…”

Identifying cytochrome P450s involved in oxidative metabolism of synthetic cannabinoid N‐(adamantan‐1‐yl)‐1‐(5‐fluoropentyl)‐1H‐indole‐3‐carboxamide (STS‐135)

“…STS‐135 is an extremely potent, third generation SCB with anecdotal evidence indicating that very little of the compound is required to generate a physiological response . Currently, there is only one study that investigated and reported metabolism of STS‐135.…”

“…STS-135 is an extremely potent, third generation SCB with anecdotal evidence indicating that very little of the compound is required to generate a physiological response. 12,19 Currently, there is only one study that investigated and reported metabolism of STS-135. According to the publication, two major hepatic metabolites of STS-135 are M25 and M21, which are mono-and di-hydroxilated metabolites, which suggests that CYPs are the major class of enzyme responsible for the oxidative metabolism of this compound.…”