Vaporization or smoking of synthetic cannabinoid-containing e-liquids or herbal formulations is a significant substance abuse problem. Although JWH-018 and other indole-derived cannabinoids that have been identified in these illicit products produce marijuana-like intoxication, they are structurally distinct from cannabinoids contained in the cannabis plant; hence, very little is known about the actual chemical exposures that occur during their use, or their pharmacology, particularly with regards to their actions at non-cannabinoid receptors and their behavioral and toxicological effects. Furthermore, the variety of structural scaffolds and analogs of synthetic cannabinoids that are being reported in these designer drug formulations continues to increase as individuals seek to become intoxicated and avoid detection, and the manufacturers and distributors of these chemicals and formulations appear to have little regard for the chemical reliability or safety of their products. Indeed, chemicals are frequently appearing in designer drug formulations that have not been previously described as cannabinoids in the scientific literature. Moreover, some of these compounds possess thermally unstable substituents of known carcinogenic activity that may be liberated during use. The proposed research will characterize synthetic cannabinoid formulations and the chemical exposures that occur during storage and use, and evaluate their pharmacological fate in in vitro and in vivo models. Emphasis will be placed on the identification of the compounds that are inhaled or produced during actual use scenarios, and the extent to which they can interact with cannabinoid CB1 and CB2 receptors, as well as with non-cannabinoid receptors, and the degree to which they produce in vivo pharmacological and toxicological effects in mouse models. The proposed studies will thereby increase knowledge of the structure-activity relationships at cannabinoid receptors and the behavioral and toxicological effects of these abused synthetic cannabinoid substances, and provide a scientific basis for evaluation of potential health concerns associated with use of these compounds.

Public Health Relevance

Synthetic cannabinoid-containing herbal blends or e-liquids are being smoked (or vaporized) by drug abusers wanting to become intoxicated. Although a variety of synthetic cannabinoids have been identified in confiscated products, many of the identified compounds undergo degradation during storage and/or chemical transformation upon the heating/combustion inherent in the route of administration. Hence, the actual chemicals to which users are exposed may differ from the cannabinoids identified in the original product. The overall goal of the proposed project is to determine and quantify compounds derived from the identified synthetic cannabinoids via pyrolysis, degradation, or metabolic processes. Parent compounds and their degradants, pyrolysis products, and metabolites will be evaluated for binding and functional activation of CB1 and CB2 cannabinoid receptors, non- cannabinoid receptors, and there in vivo pharmacology and toxicology in mouse models.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA040460-03
Application #
9451272
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Hillery, Paul
Project Start
2016-04-01
Project End
2021-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Research Triangle Institute
Department
Type
DUNS #
004868105
City
Research Triangle
State
NC
Country
United States
Zip Code
27709
Gamage, Thomas F; Farquhar, Charlotte E; Lefever, Timothy W et al. (2018) Molecular and Behavioral Pharmacological Characterization of Abused Synthetic Cannabinoids MMB- and MDMB-FUBINACA, MN-18, NNEI, CUMYL-PICA, and 5-Fluoro-CUMYL-PICA. J Pharmacol Exp Ther 365:437-446
Kevin, Richard C; Lefever, Timothy W; Snyder, Rodney W et al. (2018) Kinetic and metabolic profiles of synthetic cannabinoids NNEI and MN-18. Drug Test Anal 10:137-147
Marusich, Julie A; Wiley, Jenny L; Lefever, Timothy W et al. (2018) Finding order in chemical chaos - Continuing characterization of synthetic cannabinoid receptor agonists. Neuropharmacology 134:73-81
Bonn-Miller, Marcel O; Loflin, Mallory J E; Thomas, Brian F et al. (2017) Labeling Accuracy of Cannabidiol Extracts Sold Online. JAMA 318:1708-1709
Gamage, Thomas F; Farquhar, Charlotte E; Lefever, Timothy W et al. (2017) The great divide: Separation between in vitro and in vivo effects of PSNCBAM-based CB1 receptor allosteric modulators. Neuropharmacology 125:365-375
Thomas, Brian F; Lefever, Timothy W; Cortes, Ricardo A et al. (2017) Thermolytic Degradation of Synthetic Cannabinoids: Chemical Exposures and Pharmacological Consequences. J Pharmacol Exp Ther 361:162-171
Wiley, Jenny L; Marusich, Julie A; Thomas, Brian F (2017) Combination Chemistry: Structure-Activity Relationships of Novel Psychoactive Cannabinoids. Curr Top Behav Neurosci 32:231-248
Nguyen, Thuy; German, Nadezhda; Decker, Ann M et al. (2017) Novel Diarylurea Based Allosteric Modulators of the Cannabinoid CB1 Receptor: Evaluation of Importance of 6-Pyrrolidinylpyridinyl Substitution. J Med Chem 60:7410-7424
Nguyen, Thuy; Li, Jun-Xu; Thomas, Brian F et al. (2017) Allosteric Modulation: An Alternate Approach Targeting the Cannabinoid CB1 Receptor. Med Res Rev 37:441-474
Thomas, Brian F (2017) Interactions of Cannabinoids With Biochemical Substrates. Subst Abuse 11:1178221817711418

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