The terms K2 and Spice refer to any number of commercial products usually sold as legal marijuana. These products contain dangerous synthetic cannabinoid (SCBs) that are presumed to possess psychoactive properties similar to ?9-tetrahydrocannabinol (?9-THC), the natural cannabinoid found in marijuana. ?9-THC and SCBs both produce psychotropic actions by activating CB1 cannabinoid receptors (CB1Rs) in the CNS. However, SCBs are a chemically diverse group of compounds that are structurally distinct from ?9-THC, and thus detection of their use is difficult and has led to widespread abuse. Medical use of marijuana and ?9-THC has been shown to be safe. In marked contrast, no information is known concerning the safety or efficacy of any SCB found in K2, and reports suggest that many clinical effects of K2 products are distinct from those produced by marijuana and may present health risks. In this regard, our preliminary analysis of urine samples from SCB users by LC-MS/MS suggests that levels of SCB metabolites correlate with clinical symptoms that may be life threatening. Furthermore, we reported that several hydroxylated metabolites of SCBs retain high affinity and activity at CB1R and CB2Rs, and dramatically increase acute effects of parent SCBs. Therefore, in an individual user, the physiological effects of SCBs may represent an entourage effect caused 1) by the distinct blend of SCBs in a given product, and 2) further influenced by the individual's metabolic capacity to transform SCBs into distinct Phase I and II active metabolites. Thus, it is important to define the metabolic profile of SCBs in humans and their biological activity at CB1Rs and CB2Rs. The goal of this project is to elucidate the biodisposition, biotransformation, and biological activity of SCBs and their metabolites at CB1Rs and CB2Rs in humans, and correlate these findings with acute and chronic adverse effects in mice. We will test the hypothesis that in vivo hydroxylation of SCBs by cytochromes P450 (CYPs) and subsequent conjugation by UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) produces a complex mixture of high affinity CB1R and CB2R agonists, antagonists, and inverse agonists. These metabolites acting in concert with parent SCBs produce the distinct pharmacologic effects and toxicity of SCBs in humans. Our interdisciplinary team will explore this hypothesis by four Specific Aims.
Aim 1 will employ LC-MS/MS to identify in human urine the primary and secondary metabolites of 9 high priority SCBs abused in K2 products. Clinical symptom profiles will also be collected for each patient. Experiments in Aim 2 will characterize the human Phase I and II enzymes responsible for the in vitro metabolism of SCBs.
In Aim 3, SCBs and their metabolites will be examined for the ability to bind to and activate human CB1Rs and CB2Rs. Finally, studies in Aim 4 will determine the pharmacokinetic profile of SCBs and determine if these compounds and their metabolites elicit cannabimimetic effects in mice. This collaborative translational project will provide information concerning the metabolism, pharmacology and toxicology of SCBs to identify likely health risks to the public.

Public Health Relevance

Synthetic cannabinoids (SCBs) are very popular emerging drugs of abuse, marketed to teens and first time drug users as 'safe' and 'legal' alternatives to marijuana. However, clinical reports have indicated that SCB use results in several symptoms that are different from marijuana and life threatening. This project will investigate chemicals produced by the breakdown of SCBs in the body that may contribute to the harmful effects of these dangerous drugs of abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
3R01DA039143-04S1
Application #
9914444
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Rapaka, Rao
Project Start
2016-05-15
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Pharmacology
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Patton, Amy L; Jones, Joseph O; Nord, Anne et al. (2018) Multi-laboratory validation of a ?9-tetrahydrocannabinol LC-MS/MS test kit designed for quantifying THC and marijuana metabolites in blood. Forensic Sci Criminol 3:
Patton, Amy L; Seely, Kathryn A; Yarbrough, Azure L et al. (2018) Altered metabolism of synthetic cannabinoid JWH-018 by human cytochrome P450 2C9 and variants. Biochem Biophys Res Commun 498:597-602
Prather, Paul L (2018) Preface to DMR special edition 'Cannabinoid receptors and ligands: therapeutic drug development and abuse potential'. Drug Metab Rev 50:1-2
Nacca, Nicholas; Schult, Rachel; Loflin, Robert et al. (2018) Coma, Seizures, Atrioventricular Block, and Hypoglycemia in an ADB-FUBINACA Body-Packer. J Emerg Med 55:788-791
Fantegrossi, William E; Wilson, Catheryn D; Berquist, Michael D (2018) Pro-psychotic effects of synthetic cannabinoids: interactions with central dopamine, serotonin, and glutamate systems. Drug Metab Rev 50:65-73
Hutchison, Rachel D; Ford, Benjamin M; Franks, Lirit N et al. (2018) Atypical Pharmacodynamic Properties and Metabolic Profile of the Abused Synthetic Cannabinoid AB-PINACA: Potential Contribution to Pronounced Adverse Effects Relative to ?9-THC. Front Pharmacol 9:1084
Adair, Linda S; Duazo, Paulita; Borja, Judith B (2018) How Overweight and Obesity Relate to the Development of Functional Limitations among Filipino Women. Geriatrics (Basel) 3:
Tai, Sherrica; Fantegrossi, William E (2017) Pharmacological and Toxicological Effects of Synthetic Cannabinoids and Their Metabolites. Curr Top Behav Neurosci 32:249-262
Crowe, Molly S; Wilson, Catheryn D; Leishman, Emma et al. (2017) The monoacylglycerol lipase inhibitor KML29 with gabapentin synergistically produces analgesia in mice. Br J Pharmacol 174:4523-4539
Ford, Benjamin M; Tai, Sherrica; Fantegrossi, William E et al. (2017) Synthetic Pot: Not Your Grandfather's Marijuana. Trends Pharmacol Sci 38:257-276

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