Jenny L. Wiley

Neutral antagonists of GPCRs remain relatively rare—indeed, a large majority of GPCR antagonists are actually inverse agonists. The synthetic cannabinoid receptor agonist (SCRA) EG‐018 was recently reported as a low efficacy cannabinoid receptor agonist. Here we report a comparative characterization of EG‐018 and 13 analogues along with extant putative neutral antagonists of CB₁. In HEK cells stably expressing human CB₁, assays for inhibition of cAMP were performed by real‐time BRET biosensor (CAMYEL), G protein cycling was quantified by [³⁵S]GTPγS binding, and stimulation of pERK was characterized by AlphaLISA (PerkinElmer). Signaling outcomes for the EG‐018 analogues were highly variable, ranging from moderate efficacy agonism with high potency, to marginal agonism at lower potency. As predicted by differing pathway sensitivities to differences in ligand efficacy, most EG‐018‐based compounds were completely inactive in pERK alone. The lowest efficacy analogue in cAMP assays, 157, had utility in antagonism assay paradigms. Developing neutral antagonists of the CB₁ receptor has been a long‐standing research goal, and such compounds would have utility both as research tools and in therapeutics. Although these results emphasize again the importance of system factors in determining signaling outcomes, some compounds characterized in this study appear among the lowest efficacy agonists described to date and therefore suggest that development of neutral antagonists is an achievable goal for CB₁.

Studies have suggested that vitamin E acetate (VEA), when used in an electronic vaping device, undergoes thermal degradation and is considered one of the main contributors in e-cigarette or vaping product use-associated lung injury (EVALI). Using a Borgwaldt 5.1 linear smoker, a SVS250 Electronic Vaporizer and two types of tank systems, VEA was analyzed for degradation products produced via the Cooperation Centre for Scientific Research Relative to Tobacco method 81 when the filter containing vaporized VEA was extracted using acetonitrile. Two of the major products identified were 2,3,5,6-tetramethyl-1,4-benzoquinone and 2,6,10,14-tetramethyl-1-pentadecene, which were confirmed using analytical standards and gas chromatography–high-resolution mass spectrometry (GC–HRMS). Additional synthesis of 4-acetoxy-2,3,5,6-tetramethyl-2,4-cyclohexadienone and subsequent characterization using nuclear magnetic resonance and GC–HRMS suggested that this is not one of the products produced. Identification of these degradants will allow future studies to quantify and examine the degradants in vivo and in vitro as biomarkers for exposure and toxicity assessment.

Recent loosening of legal restrictions on cannabis and its chemical constituents, including phytocannabinoids such as Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), has led to rapid proliferation and wide availability of products containing CBD. Although using pure CBD does not result in THC-like intoxication, it is not risk-free. In this review, we examine CBD from scientific, marketing, and regulatory perspectives. Specifically, we evaluate the evidence used to support statements concerning CBD’s real and putative medical effects and discuss misleading information that has been used in marketing approaches. Also, we explore the current legal landscape surrounding CBD. We conclude that further research is necessary to clarify legitimate therapeutic effects of CBD. Federal regulation is also necessary to assure quality, safety, and efficacy of CBD products. Until new regulations are enacted to ensure purity and label accuracy, consumers should balance any perceived benefits of CBD use against potential risks associated with using products of unknown quality.

Chronic pain is the most common reason reported for using medical cannabis. The goal of this research was to determine whether the two primary phytocannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are effective treatments for persistent inflammatory pain. In experiment 1, inflammation was induced by intraplantar injection of Complete Freund’s adjuvant (CFA). Then THC (0.0–4.0 mg/kg, i.p.) or CBD (0.0–10 mg/kg, i.p.) was administered twice daily for 3 days. On day 4, THC, CBD, or vehicle was administered, and allodynia, hyperalgesia, weight-bearing, locomotor activity, and hindpaw edema were assessed 0.5–4 hours postinjection. In experiment 2, CFA or mineral oil (no-pain control)-treated rats were given THC (2.0 mg/kg, i.p.), CBD (10 mg/kg, i.p.), or vehicle in the same manner as in experiment 1. Four hours postinjection on day 4, serum samples were taken for analysis of cytokines known to influence inflammatory pain: interleukin (IL)-1β, IL-6, IL-10, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α. THC dose-dependently reduced pain-related behaviors but did not reduce hindpaw edema, and little tolerance developed to THC’s effects. In contrast, CBD effects on inflammatory pain were minimal. THC produced little to no change in serum cytokines, whereas CBD decreased IL-1β, IL-10, and IFN-γ and increased IL-6. Few sex differences in antinociception or immune modulation were observed with either drug, but CFA-induced immune activation was significantly greater in males than females. These results suggest that THC may be more beneficial than CBD for reducing inflammatory pain in that THC maintains its efficacy with short-term treatment in both sexes and does not induce immune activation. SIGNIFICANCE STATEMENT The pain-relieving effects of cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) are examined in male and female rats with persistent inflammatory pain to determine whether individual phytocannabinoids could be a viable treatment for men and women with chronic inflammatory pain. Additionally, sex differences in the immune response to an adjuvant and to THC and CBD are characterized to provide preliminary insight into immune-related effects of cannabinoid-based therapy for pain.