Thermolytic Degradation of Synthetic Cannabinoids: Chemical Exposures and Pharmacological Consequences

Abstract

Synthetic cannabinoids are manufactured clandestinely with little quality control and are distributed as herbal "spice" for smoking or as bulk compound for mixing with a solvent and inhalation via electronic vaporizers. Intoxication with synthetic cannabinoids has been associated with seizure, excited delirium, coma, kidney damage, and other disorders. The chemical alterations produced by heating these structurally novel compounds for consumption are largely unknown. Here, we show that heating synthetic cannabinoids containing tetramethylcyclopropylring substituents produced thermal degradants with pharmacological activity that varied considerably from their parent compounds. Moreover, these degradants were formed under conditions simulating smoking. Some products of combustion retained high affinity at the cannabinoid 1 (CB 1) and CB 2 receptors, were more efficacious than (2)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55,940) in stimulating CB 1 receptor-mediated guanosine 59-O-(3-thiotriphosphate) (GTPgS) binding, and were potent in producing D 9-tetrahydrocannabinol-like effects in laboratory animals, whereas other compounds had low affinity and efficacy and were devoid of cannabimimetic activity. Degradants that retained affinity and efficacy also substituted in drug discrimination tests for the prototypical synthetic cannabinoid 1-pentyl-3-(1-naphthoyl)indole (JWH-018), and are likely to produce psychotropic effects in humans. Hence, it is important to take into consideration the actual chemical exposures that occur during use of synthetic cannabinoid formulations to better comprehend the relationships between dose and effect.

Comparison of the discriminative stimulus and response rate effects of Δ9-tetrahydrocannabinol and synthetic cannabinoids in female and male rats

“…Given that differences in pharmacokinetics cannot account for this differential pattern of sensitivity across behavioral assays (i.e., greater sensitivity of female rats to WIN55,212-2’s reinforcing effects vs. no sex differences in WIN55,212-2’s effects on response rates in the FR schedule), the possibility of underlying sex differences in pharmacodynamic factors (e.g., receptor density or distribution, hormonal influences) must be considered. Interestingly, female rats exhibited a trend towards increased sensitivity to the rate decreasing effects of a ring open degradant of A-834735, a synthetic cannabinoid with extremely high efficacy for stimulation of CB 1 receptors (Grim et al, 2016; Thomas et al, 2016). “Super” agonists such as the A-834735 degradant might be expected to be more potent in rats with lower CB 1 receptor reserves in relevant brain areas.…”

The great divide: Separation between in vitro and in vivo effects of PSNCBAM-based CB 1 receptor allosteric modulators

“…with vehicle or10 mg/kg of an allosteric modulator or 3 mg/kg rimonabant 10 min before being injected i.p. with vehicle or a cannabinoid agonist (30 mg/kg THC or 5.6 mg/kg the open ring degradant of XLR-11, a tetramethylcyclopropyl synthetic cannabinoid with high affinity and efficacy at CB 1 receptors (Thomas et al, 2017). Thirty min after injection with the agonist (40 min after allosteric modulator administration), mice were placed into individual activity chambers for a 10 min session.…”

Toxic by design? Formation of thermal degradants and cyanide from carboxamide-type synthetic cannabinoids CUMYL-PICA, 5F-CUMYL-PICA, AMB-FUBINACA, MDMB-FUBINACA, NNEI, and MN-18 during exposure to high temperatures

“…CUMYL-PICA, 5F-CUMYL-PICA, AMB-FUBINACA, MDMB-FUBINACA, NNEI, and MN-18 were heated sequentially to 200, 400, 600, and 800 °C using a 5250T thermolysis/pyrolysis probe (CDS Analytical Inc., Oxford, PA, USA), using methodology similar to that reported previously [16]. The probe was equipped with an autosampler turret coupled to a GC–MS system (Agilent Technologies, Santa Clara, CA).…”

“…For example, UR-144 and XLR-11 contain a sterically-strained tetramethylcyclopropyl ring system that opens when heated [14, 15]. These ring-opened degradants retain efficacy at CB 1 receptors, and substitute for Δ 9 -THC in drug discrimination tests in rodents [16]. Thermal degradants are noteworthy for two reasons; first, thermolysis products may play a role in the net effect of synthetic cannabinoids (toxic or otherwise), either by action on cannabinoid receptors or other hitherto uncharacterised molecular targets, and second, thermal degradants may be useful analytical targets for detection and/or confirmation of synthetic cannabinoid exposure.…”

“…While the thermal degradants of several older compounds including JWH-018, UR-144, XLR-11, and PB-22 have been described [16, 19–21], relatively few synthetic cannabinoids belonging to subsequent generations of compounds have been assessed for thermal stability. Recently, the thermal degradants of carboxamide-type synthetic cannabinoids AB-CHMINACA, AB-PINACA, and AB-FUBINACA were characterized [18].…”