Browse > Article
http://dx.doi.org/10.4062/biomolther.2020.212

Abuse Potential of Synthetic Cannabinoids: AM-1248, CB-13, and PB-22  

Hur, Kwang-Hyun (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University)
Ma, Shi-Xun (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University)
Lee, Bo-Ram (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University)
Ko, Yong-Hyun (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University)
Seo, Jee-Yeon (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University)
Ryu, Hye Won (Medicinal Chemistry Laboratory, Department of Pharmacy & Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University)
Kim, Hye Jin (Medicinal Chemistry Laboratory, Department of Pharmacy & Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University)
Yoon, Seolmin (Medicinal Chemistry Laboratory, Department of Fundamental Pharmaceutical Sciences, College of Pharmacy, Kyung Hee University)
Lee, Yong-Sup (Medicinal Chemistry Laboratory, Department of Pharmacy & Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University)
Lee, Seok-Yong (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University)
Jang, Choon-Gon (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University)
Publication Information
Biomolecules & Therapeutics / v.29, no.4, 2021 , pp. 384-391 More about this Journal
Abstract
Currently, the expanding recreational use of synthetic cannabinoids (SCBs) threatens public health. SCBs produce psychoactive effects similar to those of tetrahydrocannabinol, the main component of cannabis, and additionally induce unexpected pharmacological side effects. SCBs are falsely advertised as legal and safe, but in reality, SCB abuse has been reported to cause acute intoxication and addictive disorders. However, because of the lack of scientific evidence to elucidate their dangerous pharmacological effects, SCBs are weakly regulated and continue to circulate in illegal drug markets. In the present study, the intravenous self-administration (IVSA) paradigm was used to evaluate the abuse potential of three SCBs (AM-1248, CB-13, and PB-22) in rats. All three SCBs maintained IVSA with a large number of infusions and active lever presses, demonstrating their reinforcing effects. The increase of active lever presses was particularly significant during the early IVSA sessions, indicating the reinforcement-enhancing effects of the SCBs (AM-1248 and CB-13). The number of inactive lever presses was significantly higher in the SCB groups (AM-1248 and CB-13) than that in the vehicle group, indicating their impulsive effects. In summary, these results demonstrated that SCBs have distinct pharmacological properties and abuse potential.
Keywords
Synthetic cannabinoids; Abuse potential; Intravenous self-administration; AM-1248; CB-13; PB-22;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Uchiyama, N., Kawamura, M., Kikura-Hanajiri, R. and Goda, Y. (2012) Identification of two new-type synthetic cannabinoids, N-(1-adamantyl)-1-pentyl-1H-indole-3-carboxamide (APICA) and N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide (APINACA), and detection of five synthetic cannabinoids, AM-1220, AM-2233, AM-1241, CB-13 (CRA-13), and AM-1248, as designer drugs in illegal products. Forensic Toxicol. 30, 114-125.   DOI
2 Brianna Sheppard, A., Gross, S. C., Pavelka, S. A., Hall, M. J. and Palmatier, M. I. (2012) Caffeine increases the motivation to obtain non-drug reinforcers in rats. Drug Alcohol Depend. 124, 216-222.   DOI
3 Budney, A. J. and Hughes, J. R. (2006) The cannabis withdrawal syndrome. Curr. Opin. Psychiatry 19, 233-238.   DOI
4 Carliner, H., Brown, Q. L., Sarvet, A. L. and Hasin, D. S. (2017) Cannabis use, attitudes, and legal status in the U.S.: a review. Prev. Med. 104, 13-23.   DOI
5 Carlini, E. A. (2004) The good and the bad effects of (-) trans-delta-9-tetrahydrocannabinol (Δ9-THC) on humans. Toxicon 44, 461-467.   DOI
6 De Luca, M. A., Bimpisidis, Z., Melis, M., Marti, M., Caboni, P., Valentini, V., Margiani, G., Pintori, N., Polis, I., Marsicano, G., Parsons, L. H. and Di Chiara, G. (2015) Stimulation of in vivo dopamine transmission and intravenous self-administration in rats and mice by JWH-018, a Spice cannabinoid. Neuropharmacology 99, 705-714.   DOI
7 Dei Cas, M., Casagni, E., Arnoldi, S., Gambaro, V. and Roda, G. (2019) Screening of new psychoactive substances (NPS) by gaschromatography/time of flight mass spectrometry (GC/MS-TOF) and application to 63 cases of judicial seizure. Forensic Sci. Int. Synergy 1, 71-78.   DOI
8 Lefever, T. W., Marusich, J. A., Antonazzo, K. R. and Wiley, J. L. (2014) Evaluation of WIN 55,212-2 self-administration in rats as a potential cannabinoid abuse liability model. Pharmacol. Biochem. Behav. 118, 30-35.   DOI
9 Melvin, L. S., Milne, G. M., Johnson, M. R., Subramaniam, B., Wilken, G. H. and Howlett, A. C. (1993) Structure-activity relationships for cannabinoid receptor-binding and analgesic activity: studies of bicyclic cannabinoid analogs. Mol. Pharmacol. 44, 1008-1015.
10 Drug Enforcement Administration, Department of Justice (2016) Schedules of controlled substances: placement of PB-22, 5FPB-22, AB-FUBINACA and ADB-PINACA into schedule I. Final rule. Fed. Regist. 81, 61130-61133.
11 Garcia, K. L., Le, A. D. and Tyndale, R. F. (2014) Effect of food training and training dose on nicotine self-administration in rats. Behav. Brain Res. 274, 10-18.   DOI
12 Pertwee, R. G., Howlett, A. C., Abood, M. E., Alexander, S. P. H., Di Marzo, V., Elphick, M. R., Greasley, P. J., Hansen, H. S., Kunos, G., Mackie, K., Mechoulam, R. and Ross, R. A. (2010) International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol. Rev. 62, 588-631.   DOI
13 Tai, S. and Fantegrossi, W. E. (2014) Synthetic cannabinoids: pharmacology, behavioral effects, and abuse potential. Curr. Addict. Rep. 1, 129-136.   DOI
14 Weissman, A., Milne, G. M. and Melvin, L. S., Jr. (1982) Cannabimimetic activity from CP-47,497, a derivative of 3-phenylcyclohexanol. J. Pharmacol. Exp. Ther. 223, 516-523.
15 Wiskerke, J., Van Mourik, Y., Schetters, D., Schoffelmeer, A. and Pattij, T. (2012) On the role of cannabinoid CB1- and μ-opioid receptors in motor impulsivity. Front. Pharmacol. 3, 108.   DOI
16 Zimmermann, U. S., Winkelmann, P. R., Pilhatsch, M., Nees, J. A., Spanagel, R. and Schulz, K. (2009) Withdrawal phenomena and dependence syndrome after the consumption of "spice gold". Dtsch. Arztebl. Int. 106, 464-467.
17 Dziadulewicz, E. K., Bevan, S. J., Brain, C. T., Coote, P. R., Culshaw, A. J., Davis, A. J., Edwards, L. J., Fisher, A. J., Fox, A. J., Gentry, C., Groarke, A., Hart, T. W., Huber, W., James, I. F., Kesingland, A., La Vecchia, L., Loong, Y., Lyothier, I., McNair, K., O'Farrell, C., Peacock, M., Portmann, R., Schopfer, U., Yaqoob, M. and Zadrobilek, J. (2007) Naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone: a potent, orally bioavailable human CB1/CB2 dual agonist with antihyperalgesic properties and restricted central nervous system penetration. J. Med. Chem. 50, 3851-3856.   DOI
18 Fantegrossi, W. E., Wilson, C. D. and Berquist, M. D. (2018) Pro-psychotic effects of synthetic cannabinoids: interactions with central dopamine, serotonin, and glutamate systems. Drug Metab. Rev. 50, 65-73.   DOI
19 Hajos, N., Ledent, C. and Freund, T. F. (2001) Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus. Neuroscience 106, 1-4.   DOI
20 Krotulski, A. J., Mohr, A. L. A., Kacinko, S. L., Fogarty, M. F., Shuda, S. A., Diamond, F. X., Kinney, W. A., Menendez, M. J. and Logan, B. K. (2019) 4F-MDMB-BINACA: a new synthetic cannabinoid widely implicated in forensic casework. J. Forensic Sci. 64, 1451-1461.   DOI
21 Saribas, S. E. and Ulugol, A. (2014) Struggle with bonzai: a review on synthetic cannabinoid abuse. Turk. Med. Stud. J. 1, 86-93.
22 Langer, N., Lindigkeit, R., Schiebel, H. M., Ernst, L. and Beuerle, T. (2014) Identification and quantification of synthetic cannabinoids in 'spice-like' herbal mixtures: a snapshot of the German situation in the autumn of 2012. Drug Test. Anal. 6, 59-71.   DOI
23 Leffa, D. T., Ferreira, S. G., Machado, N. J., Souza, C. M., Rosa, F. D., de Carvalho, C., Kincheski, G. C., Takahashi, R. N., Porciuncula, L. O., Souza, D. O., Cunha, R. A. and Pandolfo, P. (2019) Caffeine and cannabinoid receptors modulate impulsive behavior in an animal model of attentional deficit and hyperactivity disorder. Eur. J. Neurosci. 49, 1673-1683.   DOI
24 Papaseit, E., Farre, M., Schifano, F. and Torrens, M. (2014) Emerging drugs in Europe. Curr. Opin. Psychiatry 27, 243-250.   DOI
25 Wise, R. A. and Koob, G. F. (2014) The development and maintenance of drug addiction. Neuropsychopharmacology 39, 254-262.   DOI
26 Berkovitz, R., Arieli, M. and Marom, E. (2011) Synthetic cannabinoids- -the new "legal high" drugs. Harefuah 150, 884-887, 937.
27 Burns, N., Theakstone, A., Zhu, H., O'Dell, L., Pearson, J., Ashton, T., Pfeffer, F. and Conlan, X. (2020) The identification of synthetic cannabinoids surface coated on herbal substrates using solid-state nuclear magnetic resonance spectroscopy. Anal. Chim. Acta 1104, 105-109.   DOI
28 Makriyannis, A. and Deng, H. (2007) Receptor selective cannabimimetic aminoalkylindoles. United States Patent US 7,173,027 B2. 2007 Feb 6.
29 Kirschmann, E. K., Pollock, M. W., Nagarajan, V. and Torregrossa, M. M. (2017) Effects of adolescent cannabinoid self-administration in rats on addiction-related behaviors and working memory. Neuropsychopharmacology 42, 989-1000.   DOI
30 Lawler, A. (2018) Cannabis, opium use part of ancient Near Eastern cultures. Science 360, 249-250.   DOI
31 Fattore, L., Cossu, G., Martellotta, C. M. and Fratta, W. (2001) Intravenous self-administration of the cannabinoid CB1 receptor agonist WIN 55,212-2 in rats. Psychopharmacology 156, 410-416.   DOI
32 Angerer, V., Mogler, L., Steitz, J. P., Bisel, P., Hess, C., Schoeder, C. T., Muller, C. E., Huppertz, L. M., Westphal, F., Schaper, J. and Auwarter, V. (2018) Structural characterization and pharmacological evaluation of the new synthetic cannabinoid CUMYL-PEGACLONE. Drug Test. Anal. 10, 597-603.   DOI
33 Banister, S. D., Stuart, J., Kevin, R. C., Edington, A., Longworth, M., Wilkinson, S. M., Beinat, C., Buchanan, A. S., Hibbs, D. E., Glass, M., Connor, M., McGregor, I. S. and Kassiou, M. (2015) Effects of bioisosteric fluorine in synthetic cannabinoid designer drugs JWH-018, AM-2201, UR-144, XLR-11, PB-22, 5F-PB-22, APICA, and STS-135. ACS Chem. Neurosci. 6, 1445-1458.   DOI
34 Behonick, G., Shanks, K. G., Firchau, D. J., Mathur, G., Lynch, C. F., Nashelsky, M., Jaskierny, D. J. and Meroueh, C. (2014) Four postmortem case reports with quantitative detection of the synthetic cannabinoid, 5F-PB-22. J. Anal. Toxicol. 38, 559-562.   DOI
35 Dresen, S., Ferreiros, N., Putz, M., Westphal, F., Zimmermann, R. and Auwarter, V. (2010) Monitoring of herbal mixtures potentially containing synthetic cannabinoids as psychoactive compounds. J. Mass Spectrom. 45, 1186-1194.   DOI
36 Altintas, M., Inanc, L., Hunca, A. N., Ektiricioglu, C., Yilmaz, N., Tuna, Z. O. and uney, R. (2019) Theory of mind, aggression and impulsivity in patients with synthetic cannabinoid use disorders: a casecontrol study. Anadolu Psikiyatri Derg. 20, 5-12.   DOI
37 Covey, D. P., Wenzel, J. M. and Cheer, J. F. (2015) Cannabinoid modulation of drug reward and the implications of marijuana legalization. Brain Res. 1628, 233-243.   DOI
38 Hermanns-Clausen, M., Kneisel, S., Szabo, B. and Auwarter, V. (2013b) Acute toxicity due to the confirmed consumption of synthetic cannabinoids: clinical and laboratory findings. Addiction 108, 534-544.   DOI
39 Gatch, M. B. and Forster, M. J. (2015) Δ9-Tetrahydrocannabinol-like effects of novel synthetic cannabinoids found on the gray market. Behav. Pharmacol. 26, 460-468.   DOI
40 Fantegrossi, W. E., Moran, J. H., Radominska-Pandya, A. and Prather, P. L. (2014) Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to Δ(9)-THC: mechanism underlying greater toxicity? Life Sci. 97, 45-54.   DOI
41 Grigg, J., Manning, V., Arunogiri, S. and Lubman, D. I. (2019) Synthetic cannabinoid use disorder: an update for general psychiatrists. Australas. Psychiatry 27, 279-283.   DOI
42 Osborne, G. B. and Fogel, C. (2008) Understanding the motivations for recreational marijuana use among adult Canadians. Subst. Use Misuse 43, 539-572; discussion 573-579, 585-587.   DOI
43 Gaoni, Y. and Mechoulam, R. (1964) Isolation, structure, and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc. 86, 1646-1647.   DOI
44 Hermanns-Clausen, M., Kneisel, S., Hutter, M., Szabo, B. and Auwarter, V. (2013a) Acute intoxication by synthetic cannabinoids--four case reports. Drug Test. Anal. 5, 790-794.   DOI
45 Heath, T. S., Burroughs, Z., Thompson, A. J. and Tecklenburg, F. W. (2012) Acute intoxication caused by a synthetic cannabinoid in two adolescents. J. Pediatr. Pharmacol. Ther. 17, 177-181.   DOI
46 Hur, K.-H., Kim, S.-E., Lee, B.-R., Ko, Y.-H., Seo, J.-Y., Kim, S.-K., Ma, S.-X., Kim, Y.-J., Jeong, Y., Pham, D. T., Trinh, Q. D., Shin, E. J., Kim, H. C., Lee, Y. S., Lee, S. Y. and Jang, C. G. (2020) 25C-NBF, a new psychoactive substance, has addictive and neurotoxic potential in rodents. Arch. Toxicol. 94, 2505-2516.   DOI
47 Inci, R., Kelekci, K. H., Oguz, N., Karaca, S., Karadas, B. and Bayrakci, A. (2017) Dermatological aspects of synthetic cannabinoid addiction. Cutan. Ocul. Toxicol. 36, 125-131.   DOI
48 Aldlgan, A. (2016) Chromatographic Analysis and Survey Studies to Evaluate the Emerging Drugs of Synthetic Cannabinoids in Scotland and Saudi Arabia. University of Glasgow.
49 Murray, R. M., Englund, A., Abi-Dargham, A., Lewis, D. A., Di Forti, M., Davies, C., Sherif, M., McGuire, P. and D'Souza, D. C. (2017) Cannabis-associated psychosis: neural substrate and clinical impact. Neuropharmacology 124, 89-104.   DOI
50 Nacca, N., Vatti, D., Sullivan, R., Sud, P., Su, M. and Marraffa, J. (2013) The synthetic cannabinoid withdrawal syndrome. J. Addict. Med. 7, 296-298.   DOI
51 Ozten, M., Erol, A., Karayilan, S., Kapudan, H., Orsel, E. S. and Kumsar, N. A. (2015) Impulsivity in bipolar and substance use disorders. Compr. Psychiatry 59, 28-32.   DOI
52 Pryce, G. and Baker, D. (2017) Antidote to cannabinoid intoxication: the CB1 receptor inverse agonist, AM251, reverses hypothermic effects of the CB1 receptor agonist, CB-13, in mice. Br. J. Pharmacol. 174, 3790-3794.   DOI
53 Solinas, M., Panlilio, L. V., Tanda, G., Makriyannis, A., Matthews, S. A. and Goldberg, S. R. (2005) Cannabinoid agonists but not inhibitors of endogenous cannabinoid transport or metabolism enhance the reinforcing efficacy of heroin in rats. Neuropsychopharmacology 30, 2046-2057.   DOI
54 Spano, M. S., Fattore, L., Cossu, G., Deiana, S., Fadda, P. and Fratta, W. (2004) CB1 receptor agonist and heroin, but not cocaine, reinstate cannabinoid-seeking behaviour in the rat. Br. J. Pharmacol. 143, 343-350.   DOI