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Background: Although use of Cannabis sativa is not associated with serious adverse effects, recreational use of aminoalkylindole (AAI) cannabinoid receptor agonists found in K2/Spice herbal blends has been reported to cause adverse cardiovascular events, including angina, arrhythmia, changes in blood pressure, ischemic stroke, and myocardial infarction. Δ 9 -Tetrahydrocannabinol (Δ 9 -THC) is the primary CB 1 agonist found in cannabis and JWH-073 is one of the AAI CB 1 agonists found in K2/Spice brands sold to the public. Methods: This study used in vitro , in vivo , and ex vivo approaches to investigate potential differences on cardiac tissue and vascular effects betweenJWH-073 and Δ 9 -THC. Male C57BL/6 mice were treated with JWH-073 or Δ 9 -THC and cardiac injury was assessed by histology. Effects of JWH-073 and Δ 9 -THC on H9C2 cell viability and ex vivo mesenteric vascular reactivity were also determined. Results: JWH-073 or Δ 9 -THC induced typical cannabinoid effects of antinociception and hypothermia but did not promote death of cardiac myocytes. No differences in cell viability were observed in cultured H9C2 cardiac myocytes after 24 h of treatment. In isolated mesenteric arteries from drug-naive animals, JWH-073 produced significantly greater maximal relaxation (96%±2% vs. 73%±5%, p <0.05) and significantly greater inhibition of phenylephrine-mediated maximal contraction (Control 174%±11%K MAX ) compared with Δ 9 -THC (50%±17% vs. 119%±16%K MAX , p <0.05). Discussion: These findings suggest that neither cannabinoid at the concentrations/dose studied caused cardiac cell death, but JWH-073 has the potential for greater vascular adverse events than Δ 9 -THC through an increased vasodilatory effect.

Introduction: Synthetic cannabinoids (SCs) are commonly found in preparations used as recreational drugs. Although severe adverse health effects are not generally associated with cannabis use, a rising number of studies document seizures and even death after SC use. In this study, a mouse model is used to investigate the hypothesis that SCs are more toxic than Δ 9 -tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis. Materials and Methods: Beginning with the SCs, JWH-073 and AM-2201, dose-response curves were generated to find the dose of each drug that was similarly efficacious to 50 mg/kg THC. Mice were given daily intraperitoneal (IP) injections of vehicle, 50 mg/kg THC, 30 mg/kg JWH-073, or 1 mg/kg AM-2201 until tolerance to the antinociceptive and hypothermic effects was complete, and then were assessed for spontaneous and antagonist-precipitated withdrawal and potential organ damage. No differences in tolerance were noted, but AM-2201 showed more rearing in the spontaneous and antagonist-precipitated withdrawal phases than either vehicle or the other two drug treatments. Histopathological examination of these mice revealed no drug-induced lesions. In a subsequent set of experiments, various doses of THC, methanandamide (mAEA), and of a variety of SCs (HU-210, CP55940, JWH-073, AM-2201, and PB-22) were given IP, and convulsions and change in body temperature were quantified. Discussion: The treatments yielded varying numbers of convulsions and a range of changes in body temperature. JWH-073 and AM-2201 produced significantly more convulsions than THC, HU-210, mAEA, or cannabidiol (CBD) (the latter two producing none). HU-210, CP55940, JWH-073, and mAEA produced greater hypothermia than THC or CBD. Convulsions and hypothermia induced by several agonists were prevented by pretreatment with a CB 1 antagonist, but not a CB 2 antagonist. Conclusions: In agreement with human studies and case reports, this study found that SCs generally produced more seizures than THC. Of particular significance was the finding that mAEA produced far greater hypothermia than THC (similar to most SCs), but unlike the SCs and THC, produced no seizures., Competing Interests: No competing financial interests exist., (© Chris S. Breivogel et al. 2020; Published by Mary Ann Liebert, Inc.)

The relationship between GDP and cannabinoid-stimulated [35S]guanosine-5'-O-(3-thiotriphosphate) ([35S]GTPgammaS) binding was investigated in rat cerebellar membranes. Kinetic analyses showed that [35S]GTPgammaS binding reached steady-state levels and that the association rate was increased by the agonist WIN 55212-2 proportional to the concentration of GDP. Dissociation of [35S]GTPgammaS occurred with two rates (t1/2 = 7 and 170 min), and WIN 55212-2 increased the proportion of sites exhibiting the faster rate. Without GDP, [35S]GTPgammaS bound to membranes with high and low affinity, and WIN 55212-2 had no effect. With 30 microM GDP, [35S]GTPgammaS bound to low and intermediate affinity sites, and WIN 55212-2 induced high affinity [35S]GTPgammaS binding without affecting low affinity sites. GDP competed for high affinity [35S]GTPgammaS binding with high and intermediate affinity in the absence of WIN 55212-2 and with high and low affinity in the presence of WIN 55212-2. Cannabinoid ligands displayed differential abilities to maximally stimulate [35S]GTPgammaS binding in the presence of GDP. Efficacy differences among ligands increased with increasing GDP concentrations. GDP competition curves revealed that agonists induced low affinity GDP Ki values that were proportional to agonist Emax values, indicating that agonist efficacy is determined by displacement of GDP from G-proteins.