Narrative Review of the Pharmacodynamics, Pharmacokinetics, and Toxicities
of Illicit Synthetic Cannabinoid Receptor Agonists

Matilda      Lea Houston; Jody      Morgan; Celine      Kelso
Abstract

Background: Synthetic cannabinoid receptor agonists (SCRAs) are the most diverse class of new psychoactive substances worldwide, with approximately 300 unique SCRAs identified to date. While the use of this class of drug is not particularly prevalent, SCRAs are associated with several deaths every year due to their severe toxicity.
Methods: A thorough examination of the literature identified 15 new SCRAs with a significant clinical impact between 2015 and 2021.
Results: These 15 SCRAs have been implicated in 154 hospitalizations and 209 deaths across the US, Europe, Asia, and Australasia during this time period.
Conclusion: This narrative review provides pharmacodynamic, pharmacokinetic, and toxicologic data for SCRAs as a drug class, including an in-depth review of known pharmacological properties of 15 recently identified and emerging SCRAs for the benefit of researchers, policy makers, and clinicians who wish to be informed of developments in this field.
Keywords: Synthetic cannabinoids, spice, NPS, toxicity, pharmacology, SCRA.
Graphical Abstract

[1]
 United Nations Office on Drugs and Crime (UNODC).  2018. Available From: https://www.unodc.org/documents/scientific/NPS_leaflet_2018_EN.PDF

[2]
Alcohol and Drug Foundation Synthetic Cannabis., 2020. Available From: https://adf.org.au/drug-facts/synthetic-cannabis/

[3]
Darke, S.; Banister, S.; Farrell, M.; Duflou, J.; Lappin, J. ‘Synthetic cannabis’: A dangerous misnomer. Int. J. Drug Policy,  2021, 98, 103396.
 [http://dx.doi.org/10.1016/j.drugpo.2021.103396] [PMID:  34343944]

[4]
United Nations Office on Drugs and Crime (UNODC) Share of NPS stimulants and synthetic cannabinoids remains stable while opioids continue to increase., 2021. Available From: https://www.unodc.org/LSS/Announcement/Details/d45a4db1-4f64-447e-818c-35ce7a2e2278

[5]
Hudson, S.; Ramsey, J. The emergence and analysis of synthetic cannabinoids. Drug Test. Anal.,  2011, 3(7-8), 466-478.
 [http://dx.doi.org/10.1002/dta.268] [PMID:  21337724]

[6]
Sholler, D.J.; Huestis, M.A.; Amendolara, B.; Vandrey, R.; Cooper, Z.D. Therapeutic potential and safety considerations for the clinical use of synthetic cannabinoids. Pharmacol. Biochem. Behav.,  2020, 199, 173059.
 [http://dx.doi.org/10.1016/j.pbb.2020.173059] [PMID:  33086126]

[7]
Correia, B.; Fernandes, J.; Botica, M.J.; Ferreira, C.; Quintas, A. Novel psychoactive substances: The razor’s edge between therapeutical potential and psychoactive recreational misuse. Medicines  ,  2022, 9(3), 19.
 [http://dx.doi.org/10.3390/medicines9030019] [PMID:  35323718]

[8]
De Luca, M.A.; Fattore, L. Therapeutic use of synthetic cannabinoids: Still an open issue? Clin. Ther.,  2018, 40(9), 1457-1466.
 [http://dx.doi.org/10.1016/j.clinthera.2018.08.002] [PMID:  30180974]

[9]
Pagano, C.; Navarra, G.; Coppola, L.; Avilia, G.; Bifulco, M.; Laezza, C. Cannabinoids: Therapeutic use in clinical practice. Int. J. Mol. Sci.,  2022, 23(6), 3344.
 [http://dx.doi.org/10.3390/ijms23063344] [PMID:  35328765]

[10]
Basavarajappa, B.; Subbanna, S. Potential mechanisms underlying the deleterious effects of synthetic cannabinoids found in spice/K2 products. Brain Sci.,  2019, 9(1), 14.
 [http://dx.doi.org/10.3390/brainsci9010014] [PMID:  30654473]

[11]
Gunderson, E.W.; Haughey, H.M.; Ait-Daoud, N.; Joshi, A.S.; Hart, C.L. A survey of synthetic cannabinoid consumption by current cannabis users. Subst. Abus.,  2014, 35(2), 184-189.
 [http://dx.doi.org/10.1080/08897077.2013.846288] [PMID:  24821356]

[12]
Giorgetti, A.; Busardò, F.P.; Tittarelli, R.; Auwärter, V.; Giorgetti, R. Post-mortem toxicology: A systematic review of death cases involving synthetic cannabinoid receptor agonists. Front. Psychiatry,  2020, 11, 464.
 [http://dx.doi.org/10.3389/fpsyt.2020.00464] [PMID:  32523555]

[13]
European Monitoring Centre for Drugs and Drug Addiction	(EMCDDA). \ National report; Hungary. Lisbon, , 2015; p. 17.

[14]
Johnston, L.D.; O’Malley, P.M.; Bachman, J.G.; Schulenberg, J.E.; Miech, R.A.  Monitoring the Future national survey results on drug	use, 1975-2013; Institute for Social Research, University of
	Michigan: Ann Arbor, MI , 2014;  I, , . 

[15]
Australian Institute of Health and Welfare. National Drug Strategy	Household Survey (NDSHS) 2019; AIHW: Canberra, , 2020. 

[16]
Australian Institute of Health and Welfare. National Drug Strategy	Household Survey (NDSHS) 2016; AIHW: Canberra 2017.

[17]
European Monitoring Centre for Drugs and Drug Addiction	(EMCDDA). In: Synthetic cannabinoids in Europe; Perspectives on Drugs: Lisbon, 2017. 

[18]
 European Monitoring Centre for Drugs and Drug Addiction	(EMCDDA). European Union: EMCDDA technical report on the	new psychoactive substance methyl 3,3-dimethyl-2-{[1-(pent-4-en-	1-yl)-1H-indazole-3-carbonyl]amino}butanoate (MDMB-4en-	PINACA); Asia News Monitor: Bangkok , 2020. 

[19]
New Zealand, EACD AB-FUBINACA and AMB-FUBINACA:	Report to the Expert Advisory Committee on Drugs 2018.

[20]
Toronto’s Drug Checking Service. In: “New” synthetic cannabinoid found in opioid samples: ACHMINACA; , 2020.  Available From: https://drugchecking.cdpe.org/alert/achminaca/ [Accessed on: March 28, 2021]

[21]
Barratt, M.J.; Cakic, V.; Lenton, S. Patterns of synthetic cannabinoid use in Australia. Drug Alcohol Rev.,  2013, 32(2), 141-146.
 [http://dx.doi.org/10.1111/j.1465-3362.2012.00519.x] [PMID:  23043552]

[22]
Loeffler, G.; Delaney, E.; Hann, M. International trends in spice use: Prevalence, motivation for use, relationship to other substances, and perception of use and safety for synthetic cannabinoids. Brain Res. Bull.,  2016, 126(Pt. 1), 8-28.
 [http://dx.doi.org/10.1016/j.brainresbull.2016.04.013] [PMID:  27108542]

[23]
Castaneto, M.S.; Gorelick, D.A.; Desrosiers, N.A.; Hartman, R.L.; Pirard, S.; Huestis, M.A. Synthetic cannabinoids: Epidemiology, pharmacodynamics, and clinical implications. Drug Alcohol Depend.,  2014, 144, 12-41.
 [http://dx.doi.org/10.1016/j.drugalcdep.2014.08.005] [PMID:  25220897]

[24]
Australian Institute of Health and Welfare. New (and emerging)	psychoactive substances.  2020. Available From:  https://www.aihw.gov.au/reports/alcohol/alcohol-tobacco-other-drugs-australia/contents/drug-types/new-and-emerging-psychoactive-substances#synthetic-cannabinoids(Accessed 10	August 2021).

[25]
Darke, S.; Duflou, J.; Farrell, M.; Peacock, A.; Lappin, J. Characteristics and circumstances of synthetic cannabinoid-related death. Clin. Toxicol. (Phila.),  2020, 58(5), 368-374.
 [http://dx.doi.org/10.1080/15563650.2019.1647344] [PMID:  31389266]

[26]
Adams, A.J.; Banister, S.D.; Irizarry, L.; Trecki, J.; Schwartz, M.; Gerona, R. “Zombie” outbreak caused by the synthetic cannabinoid AMB-FUBINACA in New York. N. Engl. J. Med.,  2017, 376(3), 235-242.
 [http://dx.doi.org/10.1056/NEJMoa1610300] [PMID:  27973993]

[27]
Alon, M.H.; Saint-Fleur, M.O. Synthetic cannabinoid induced acute respiratory depression: Case series and literature review. Respir. Med. Case Rep.,  2017, 22, 137-141.
 [http://dx.doi.org/10.1016/j.rmcr.2017.07.011] [PMID:  28794966]

[28]
Armenian, P.; Darracq, M.; Gevorkyan, J.; Clark, S.; Kaye, B.; Brandehoff, N.P. Intoxication from the novel synthetic cannabinoids AB-PINACA and ADB-PINACA: A case series and review of the literature.  Neuropharmacology, ,  2018, 134(Pt A ), 82-91.
 [http://dx.doi.org/10.1016/j.neuropharm.2017.10.017 ] [PMID:  29037744]

[29]
] European Monitoring Centre for Drugs and Drug Addiction	(EMCDDA). EMCDDA initial report on the new psychoactive	substance 4F-MDMB-BICA;, 2021.

[30]
Kant, A.; Mong, R.; Tan, H.H. Accidental ingestion of a novel psychoactive substance: A case report. Cureus,  2020, 12(10), e11185-e11185.
 [http://dx.doi.org/10.7759/cureus.11185] [PMID:  33269117]

[31]
Moritz, E.; Austin, C.; Wahl, M.; DesLauriers, C.; Navon, L.; Walblay, K.; Hendrickson, M.; Phillips, A.; Kerins, J.; Pennington, A.F.; Lavery, A.M.; El Zahran, T.; Kauerauf, J.; Yip, L.; Thomas, J.; Layden, J. Notes from the Field: Outbreak of severe illness linked to the vitamin K antagonist brodifacoum and use of synthetic cannabinoids - illinois, March-April 2018. MMWR Morb. Mortal. Wkly. Rep.,  2018, 67(21), 607-608.
 [http://dx.doi.org/10.15585/mmwr.mm6721a4] [PMID:  29851941]

[32]
Rose, D.Z.; Guerrero, W.R.; Mokin, M.V.; Gooch, C.L.; Bozeman, A.C.; Pearson, J.M.; Burgin, W.S. Hemorrhagic stroke following use of the synthetic marijuana “spice”. Neurology,  2015, 85(13), 1177-1179.
 [http://dx.doi.org/10.1212/WNL.0000000000001973] [PMID:  26320200]

[33]
Aydin, S.; Yuksel, O.; Aydin, A.; Kizilkilic, O.; Celik, S. Intracerebral hemorrhage with multiple intracranial arterial stenoses in a synthetic cannabinoid “Spice” user. Asian J. Neurosurg.,  2018, 13(2), 522-524.
 [http://dx.doi.org/10.4103/ajns.AJNS_48_16] [PMID:  29682077]

[34]
Aygün, A. Katipoğlu, B.; Imamoglu, M.; Kilic, M.; Karapolat, B.S.; Türkyılmaz, A. Acute respiratory distress syndrome and pneumothorax after synthetic cannabinoid intoxication. Eurasian J. Emerg. Med.,  2017, 16(2), 86-87.
 [http://dx.doi.org/10.5152/eajem.2017.00719]

[35]
El Zahran, T.; Gerona, R.; Morgan, B.W.; Pomerleau, A.C. A novel synthetic cannabinoid (Cumyl-4-cyano-BINACA) resulting in hyperthermia, rhabdomyolysis, and renal failure in a 29-year-old patient: it’s not meningitis. Clin. Toxicol. ,  2019, 57(6), 421-422.
 [http://dx.doi.org/10.1080/15563650.2018.1534241] [PMID:  30442067]

[36]
Krotulski, A.J.; Bishop-Freeman, S.C.; Mohr, A.L.A.; Logan, B.K. Evaluation of synthetic cannabinoid metabolites in human blood in the absence of parent compounds: A stability assessment. J. Anal. Toxicol.  ,  2021, 45(1), 60-68. a
 [http://dx.doi.org/10.1093/jat/bkaa054] [PMID:  32435808]

[37]
Lam, R.P.K.; Tang, M.H.Y.; Leung, S.C.; Chong, Y.K.; Tsui, M.S.H.; Mak, T.W.L. Supraventricular tachycardia and acute confusion following ingestion of e-cigarette fluid containing AB-FUBINACA and ADB-FUBINACA: A case report with quantitative analysis of serum drug concentrations. Clin. Toxicol. (Phila.),  2017, 55(7), 662-667.
 [http://dx.doi.org/10.1080/15563650.2017.1307385] [PMID:  28393558]

[38]
McIlroy, G.; Ford, L.; Khan, J.M. Acute myocardial infarction, associated with the use of a synthetic adamantyl-cannabinoid: A case report. BMC Pharmacol. Toxicol.,  2016, 17(1), 2-2.
 [http://dx.doi.org/10.1186/s40360-016-0045-1] [PMID:  26772803]

[39]
Kleis, J.; Germerott, T.; Halter, S.; Héroux, V.; Roehrich, J.; Schwarz, C.S.; Hess, C. The synthetic cannabinoid 5F-MDMB-PICA: A case series. Forensic Sci. Int.,  2020, 314, 110410.
 [http://dx.doi.org/10.1016/j.forsciint.2020.110410] [PMID:  32683270]

[40]
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.; Logan, B.K. 4F‐MDMB BINACA: A new synthetic cannabinoid widely implicated in forensic casework. J. Forensic Sci.,  2019, 64(5), 1451-1461.
 [http://dx.doi.org/10.1111/1556-4029.14101] [PMID:  31260580]

[41]
Krotulski, A.J.; Mohr, A.L.A.; Diamond, F.X.; Logan, B.K. Detection and characterization of the new synthetic cannabinoid APP‐BINACA in forensic casework. Drug Test. Anal.,  2020, 12(1), 136-144.
 [http://dx.doi.org/10.1002/dta.2698] [PMID:  31788963]

[42]
Krotulski, A.J.; Cannaert, A.; Stove, C.; Logan, B.K. The next generation of synthetic cannabinoids: Detection, activity, and potential toxicity of pent‐4en and but‐3en analogues including MDMB‐4en‐PINACA.[b Drug Test. Anal.,  2021, 13(2), 427-438.
 [http://dx.doi.org/10.1002/dta.2935] [PMID:   32997377]

[43]
Morrow, P.L.; Stables, S.; Kesha, K.; Tse, R.; Kappatos, D.; Pandey, R.; Russell, S.; Linsell, O.; McCarthy, M.J.; Spark, A.; Vertes, D.; Triggs, Y.; McCarthy, S.; Cuthers, N.; Massey, R. An outbreak of deaths associated with AMB-FUBINACA in Auckland NZ. E. Clin. Med.,  2020, 25, 100460.
 [http://dx.doi.org/10.1016/j.eclinm.2020.100460] [PMID:  32743487]

[44]
Truver, M.T.; Watanabe, S. 5F-MDMB-PICA metabolite identification and cannabinoid receptor activity. Drug Test. Anal.,  2020, 12(1), 127-135.

[45]
Yeter, O. Simultaneous determination of 4F-MDMB BINACA, a new synthetic cannabinoid, and its metabolites in human blood samples by LC-MS/MS. J. Turkish Chem. Soc. Sect. A: Chemistry,  2020, 7(3), 827-832.
 [http://dx.doi.org/10.18596/jotcsa.770427]

[46]
Ralphs, R.; Williams, L.; Askew, R.; Norton, A. Adding Spice to the Porridge: The development of a synthetic cannabinoid market in an English prison. Int. J. Drug Policy,  2017, 40, 57-69.
 [http://dx.doi.org/10.1016/j.drugpo.2016.10.003] [PMID:  27955961]

[47]
User Voice. Spice: The Bird Killer. 2016.

[48]
Chambers, R. SPICE is now the most popular drug in UK prisons. Focus On; ILLY Systems: London, 2016. 

[49]
Spaderna, M.; Addy, P.H.; D’Souza, D.C. Spicing things up: Synthetic cannabinoids. Psychopharmacology (Berl.),  2013, 228(4), 525-540.
 [http://dx.doi.org/10.1007/s00213-013-3188-4] [PMID:  23836028]

[50]
Tettey, J.N.A.; Crean, C.; Rodrigues, J.; Angeline Yap, T.W.; Lee Wendy Lim, J.; Shirley Lee, H.Z.; Ching Ong, M. United nations office on drugs and crime: Recommended methods for the identification and analysis of synthetic cannabinoid receptor agonists in seized materials. Forensic Sci. Int.: Synergy,  2021, 3, 100129-100129.
 [http://dx.doi.org/10.1016/j.fsisyn.2020.11.003] [PMID:  33665591]

[51]
Musah, R.A.; Domin, M.A.; Walling, M.A.; Shepard, J.R.E. Rapid identification of synthetic cannabinoids in herbal samples via direct analysis in real time mass spectrometry. Rapid Commun. Mass Spectrom.,  2012, 26(9), 1109-1114.
 [http://dx.doi.org/10.1002/rcm.6205] [PMID:  22467461]

[52]
Norman, C.; Walker, G.; McKirdy, B.; McDonald, C.; Fletcher, D.; Antonides, L.H.; Sutcliffe, O.B.; Nic Daéid, N.; McKenzie, C. Detection and quantitation of synthetic cannabinoid receptor agonists in infused papers from prisons in a constantly evolving illicit market. Drug Test. Anal.,  2020, 12(4), 538-554.
 [http://dx.doi.org/10.1002/dta.2767] [PMID:  31944624]

[53]
Ford, L.; Berg, J. Annals Express: Analytical evidence to show letters impregnated with novel psychoactive substances (NPS) are a means of getting drugs to inmates within the UK prison service. Ann. Clin. Biochem.,  2018, 55, 4563218767462.
 [http://dx.doi.org/10.1177/0004563218767462]

[54]
 National Institute on Drug Abuse. Synthetic Cannabinoids (K2/Spice) DrugFacts., 2018. Available From:  https://www.drugabuse.gov/publications/drugfacts/synthetic-cannabinoids-k2spice [Accessed on: March 17, 2021].

[55]
Apirakkan, O.; Frinculescu, A.; Denton, H.; Shine, T.; Cowan, D.; Abbate, V.; Frascione, N. Isolation, detection and identification of synthetic cannabinoids in alternative formulations or dosage forms. Forensic Chem.,  2020, 18, 100227.
 [http://dx.doi.org/10.1016/j.forc.2020.100227]

[56]
Lefever, T.W.; Marusich, J.A.; Thomas, B.F.; Barrus, D.G.; Peiper, N.C.; Kevin, R.C.; Wiley, J.L. Vaping synthetic cannabinoids: A novel preclinical model of e-cigarette use in mice. Subst. Abuse,  2017, 11, 1178221817701739.
 [http://dx.doi.org/10.1177/1178221817701739] [PMID:  28469427]

[57]
Evans, D.G. Medical fraud, mislabeling, contamination: All common in CBD products. Mo. Med.,  2020, 117(5), 394-399.
 [PMID:  33311737]

[58]
Poklis, J.L.; Mulder, H.A.; Peace, M.R. The unexpected identification of the cannabimimetic, 5F-ADB, and dextromethorphan in commercially available cannabidiol e-liquids. Forensic Sci. Int.,  2019, 294, e25-e27.
 [http://dx.doi.org/10.1016/j.forsciint.2018.10.019] [PMID:  30442388]

[59]
McCarberg, B.H.; Barkin, R.L. The future of cannabinoids as analgesic agents: A pharmacologic, pharmacokinetic, and pharmacodynamic overview. Am. J. Ther.,  2007, 14(5), 475-483.
 [http://dx.doi.org/10.1097/MJT.0b013e3180a5e581] [PMID:  17890938]

[60]
Abral, G.A.; Raborn, E.S.; Griffin, L.; Dennis, J. CB2 receptors in the brain: Role in central immune function. Br. J. Pharmacol.,  2008, 153(2), 240-251.

[61]
Onaivi, E.S.; Ishiguro, H.; Gong, J.P.; Patel, S.; Perchuk, A.; Meozzi, P.A.; Myers, L.; Mora, Z.; Tagliaferro, P.; Gardner, E.; Brusco, A.; Akinshola, B.E.; Liu, Q.R.; Hope, B.; Iwasaki, S.; Arinami, T.; Teasenfitz, L.; Uhl, G.R. Discovery of the presence and functional expression of cannabinoid CB2 receptors in brain. Ann. N. Y. Acad. Sci.,  2006, 1074(1), 514-536.
 [http://dx.doi.org/10.1196/annals.1369.052] [PMID:  17105950]

[62]
Van Sickle, M.D.; Duncan, M.; Kingsley, P.J.; Mouihate, A.; Urbani, P.; Mackie, K.; Stella, N.; Makriyannis, A.; Piomelli, D.; Davison, J.S.; Marnett, L.J.; Di Marzo, V.; Pittman, Q.J.; Patel, K.D.; Sharkey, K.A. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science,  2005, 310(5746), 329-332.
 [http://dx.doi.org/10.1126/science.1115740] [PMID:  16224028]

[63]
Pertwee, R.G. The diverse CB 1 and CB 2 receptor pharmacology of three plant cannabinoids: Δ 9 -tetrahydrocannabinol, cannabidiol and Δ 9 -tetrahydrocannabivarin. Br. J. Pharmacol.,  2008, 153(2), 199-215.
 [http://dx.doi.org/10.1038/sj.bjp.0707442] [PMID:  17828291]

[64]
Zou, S.; Kumar, U. Cannabinoid receptors and the endocannabinoid system: Signaling and function in the central nervous system. Int. J. Mol. Sci.,  2018, 19(3), 833.
 [http://dx.doi.org/10.3390/ijms19030833] [PMID:  29533978]

[65]
Ginsburg, B.C.; Schulze, D.R.; Hruba, L.; McMahon, L.R. JWH-018 and JWH-073: Δ⁹-tetrahydrocannabinol-like discriminative stimulus effects in monkeys. J. Pharmacol. Exp. Ther.,  2012, 340(1), 37-45.
 [http://dx.doi.org/10.1124/jpet.111.187757] [PMID:  21965552]

[66]
Cannaert, A.; Sparkes, E.; Pike, E.; Luo, J.L.; Fang, A.; Kevin, R.C.; Ellison, R.; Gerona, R.; Banister, S.D.; Stove, C.P. Synthesis and in vitro Cannabinoid Receptor 1 Activity of Recently Detected Synthetic Cannabinoids 4F-MDMB-BICA, 5F-MPP-PICA, MMB-4en-PICA, CUMYL-CBMICA, ADB-BINACA, APP-BINACA, 4F-MDMB-BINACA, MDMB-4en-PINACA, A-CHMINACA, 5F-AB-P7AICA, 5F-MDMB-P7AICA, and 5F-AP7AICA. ACS Chem. Neurosci.,  2020, 11(24), 4434-4446.
 [http://dx.doi.org/10.1021/acschemneuro.0c00644] [PMID:  33253529]

[67]
Vandrey, R.; Dunn, K.E.; Fry, J.A.; Girling, E.R. A survey study to characterize use of Spice products (synthetic cannabinoids). Drug Alcohol Depend.,  2012, 120(1-3), 238-241.
 [http://dx.doi.org/10.1016/j.drugalcdep.2011.07.011] [PMID:  21835562]

[68]
Zimmermann, U.S.; Winkelmann, P.R.; Pilhatsch, M.; Nees, J.A.; Spanagel, R.; Schulz, K. Withdrawal phenomena and dependence syndrome after the consumption of “spice gold”. Dtsch. Arztebl. Int.,  2009, 106(27), 464-467.
 [http://dx.doi.org/10.3238/arztebl.2009.0464] [PMID:  19652769]

[69]
Tai, S.; Fantegrossi, W.E. Pharmacological and Toxicological Effects of Synthetic Cannabinoids and Their Metabolites. Neuropharmacology of New Psychoactive Substances (NPS): The Science Behind the Headlines; Baumann, M.H.; Glennon, R.A; Wiley, J.L., Ed.; Springer International Publishing: Cham, 2017, pp. 249-262.

[70]
Gamage, T.F.; Farquhar, C.E.; Lefever, T.W.; Marusich, J.A.; Kevin, R.C.; McGregor, I.S.; Wiley, J.L.; Thomas, B.F. 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.,  2018, 365(2), 437-446.
 [http://dx.doi.org/10.1124/jpet.117.246983] [PMID:  29549157]

[71]
Banister, S.D.; Longworth, M.; Kevin, R.; Sachdev, S.; Santiago, M.; Stuart, J.; Mack, J.B.C.; Glass, M.; McGregor, I.S.; Connor, M.; Kassiou, M. pharmacology of valinate and tert -leucinate Synthetic cannabinoids 5F-AMBICA, 5F-AMB, 5F-ADB, AMB-FUBINACA, MDMB-FUBINACA, MDMB-CHMICA, and their analogues. ACS Chem. Neurosci.,  2016, 7(9), 1241-1254.
 [http://dx.doi.org/10.1021/acschemneuro.6b00137] [PMID:  27421060]

[72]
Takeda, A.; Doi, T.; Asada, A.; Suzuki, T.; Yuzawa, K.; Ando, H.; Kubo, Y.; Nagasawa, A.; Kaihoko, F.; Hasegawa, Y.; Tanaka, K.; Igarashi, K.; Maeno, T.; Suzuki, A.; Shimizu, S.; Uemura, N.; Nakajima, J.; Suzuki, J.; Tagami, T. Evaluation of carboxamide-type synthetic cannabinoids on the functional activities at cannabinoid receptors and biological effects via inhalation exposure test. Forensic Toxicol.,  2020, 38(2), 455-464.
 [http://dx.doi.org/10.1007/s11419-020-00534-x]

[73]
Antonides, L.H.; Cannaert, A.; Norman, C. NicDáeid, N.; Sutcliffe, O.B.; Stove, C.P.; McKenzie, C. Shape matters: The application of activity‐based in vitro bioassays and chiral profiling to the pharmacological evaluation of synthetic cannabinoid receptor agonists in drug‐infused papers seized in prisons. Drug Test. Anal.,  2021, 13(3), 628-643.
 [http://dx.doi.org/10.1002/dta.2965] [PMID:  33161649]

[74]
Grafinger, K.E.; Cannaert, A.; Ametovski, A.; Sparkes, E.; Cairns, E.; Banister, S.D.; Auwärter, V.; Stove, C.P. Systematic evaluation of a panel of 30 synthetic cannabinoid receptor agonists structurally related to MMB-4en-PICA, MDMB-4en-PINACA, ADB-4en-PINACA, and MMB-4CN-BUTINACA using a combination of binding and different CB1 receptor activation assays-Part II: Structure activity relationship assessment via a β-arrestin recruitment assay. Drug Test. Anal.,  2021, 13(7), 1402-1411.

[75]
Lie, W.; Cheong, E.J.Y.; Goh, E.M.L.; Moy, H.Y.; Cannaert, A.; Stove, C.P.; Chan, E.C.Y. Diagnosing intake and rationalizing toxicities associated with 5F-MDMB-PINACA and 4F-MDMB-BINACA abuse. Arch. Toxicol.,  2021, 95(2), 489-508.
 [http://dx.doi.org/10.1007/s00204-020-02948-3] [PMID:  33236189]

[76]
R-Chemicals Website MPHP-2201 Cannabinoids - New Research Chemicals Shop - R-Chemicals.  Available From:https://r-chemicals.com/rc/mphp-2201/#:~:text=MPHP%2D2201%20Is%20an%20analogue,(CB2)%20receptors%2C%20respectively(Accessed 10 March 2021).

[77]
Haschimi, B.; Grafinger, K.E.; Pulver, B.; Psychou, E.; Halter, S.; Huppertz, L.M.; Westphal, F.; Pütz, M.; Auwärter, V. New synthetic cannabinoids carrying a cyclobutyl methyl side chain: Human Phase I metabolism and data on human cannabinoid receptor 1 binding and activation of Cumyl‐CBMICA and Cumyl‐CBMINACA. Drug Test. Anal.,  2021, 13(8), 1499-1515.
 [http://dx.doi.org/10.1002/dta.3038] [PMID:  33788409]

[78]
Drug Enforcement Agency. Announcement of a newly identified	synthetic cannabinoid 4CN-AB-BUTICA. 2021.	[79] Drug Enforcement Agency. Announcement of a Newly Identified	Synthetic Cannabinoid 4-CN-AMB-BUTINACA. 2021.

[79]

2020.

[80]
Grotenhermen, F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin. Pharmacokinet.,  2003, 42(4), 327-360.
 [http://dx.doi.org/10.2165/00003088-200342040-00003] [PMID:  12648025]

[81]
Auwärter, V.; Dresen, S.; Weinmann, W.; Müller, M.; Pütz, M.; Ferreirós, N. ‘Spice’ and other herbal blends: Harmless incense or cannabinoid designer drugs? J. Mass Spectrom.,  2009, 44(5), 832-837.
 [http://dx.doi.org/10.1002/jms.1558] [PMID:  19189348]

[82]
Teske, J.; Weller, J.P.; Fieguth, A.; Rothämel, T.; Schulz, Y.; Tröger, H.D. Sensitive and rapid quantification of the cannabinoid receptor agonist naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018) in human serum by liquid chromatography–tandem mass spectrometry. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.,  2010, 878(27), 2659-2663.
 [http://dx.doi.org/10.1016/j.jchromb.2010.03.016] [PMID:  20378423]

[83]
Hutter, M.; Moosmann, B.; Kneisel, S.; Auwärter, V. Characteristics of the designer drug and synthetic cannabinoid receptor agonist AM-2201 regarding its chemistry and metabolism. J. Mass Spectrom.,  2013, 48(7), 885-894.
 [http://dx.doi.org/10.1002/jms.3229] [PMID:  23832945]

[84]
Grigoryev, A.; Kavanagh, P.; Melnik, A. The detection of the urinary metabolites of 1-[(5-fluoropentyl)-1H-indol-3-yl]-(2-iodophenyl)methanone (AM-694), a high affinity cannabimimetic, by gas chromatography - mass spectrometry. Drug Test. Anal.,  2013, 5(2), 110-115.
 [http://dx.doi.org/10.1002/dta.1336] [PMID:  22522907]

[85]
Grigoryev, A.; Kavanagh, P.; Melnik, A. The detection of the urinary metabolites of 3-[(adamantan-1-yl)carbonyl]-1-pentylindole (AB-001), a novel cannabimimetic, by gas chromatography-mass spectrometry. Drug Test. Anal.,  2012, 4(6), 519-524.
 [http://dx.doi.org/10.1002/dta.350] [PMID:  22102533]

[86]
Giorgetti, A.; Mogler, L.; Haschimi, B.; Halter, S.; Franz, F.; Westphal, F.; Fischmann, S.; Riedel, J.; Pütz, M.; Auwärter, V. Detection and phase I metabolism of the 7‐AB‐azaindole‐derived synthetic cannabinoid 5F‐AB‐P7AICA including a preliminary pharmacokinetic evaluation. Drug Test. Anal.,  2020, 12(1), 78-91.
 [http://dx.doi.org/10.1002/dta.2692] [PMID:  31476105]

[87]
Traynor, K. Illinois hospitals cope with outbreak of bleeding linked to tainted cannabinoids. Am. J. Health Syst. Pharm.,  2018, 75(11), 728-732.
 [http://dx.doi.org/10.2146/news180032] [PMID:  29695484]

[88]
 United Nations Office on Drugs and Crime (UNODC). World Drug Report., 2020.

[89]
Abbate, V.; Schwenk, M.; Presley, B.C.; Uchiyama, N. The ongoing challenge of novel psychoactive drugs of abuse. Part I. Synthetic cannabinoids (IUPAC Technical Report). Pure Appl. Chem.,  2018, 90(8), 1255-1282.
 [http://dx.doi.org/10.1515/pac-2017-0605]

[90]
Sherwood, S. Synthetic cannabis users gambling with their lives after a 'bad batch; , 2018.  Available From:https://www.stuff.co.nz/national/107268892/warning-issued-over-synthetic-cannabis-use-after-10-people-hospitalised [Accessed on:	March 28, 2021].

[91]
Lobato-Freitas, C.; Brito-da-Costa, A.M.; Dinis-Oliveira, R.J.; Carmo, H.; Carvalho, F.; Silva, J.P.; Dias-da-Silva, D. overview of synthetic cannabinoids ADB-FUBINACA and AMB-FUBINACA: Clinical, analytical, and forensic implications. Pharmaceuticals,  2021, 14(3), 186.
 [http://dx.doi.org/10.3390/ph14030186] [PMID:  33669071]

[92]
Presley, B.C.; Castaneto, M.S.; Logan, B.K.; Jansen-Varnum, S.A. Assessment of synthetic cannabinoid FUB‐AMB and its ester hydrolysis metabolite in human liver microsomes and human blood samples using UHPLC–MS/MS. Biomed. Chromatogr.,  2020, 34(9), e4884.
 [http://dx.doi.org/10.1002/bmc.4884] [PMID:  32415732]

[93]
Xu, D.; Zhang, W.; Li, J.; Wang, J.; Qin, S.; Lu, J. Analysis of AMB-FUBINACA biotransformation pathways in human liver microsome and zebrafish systems by liquid chromatography-high resolution mass spectrometry. Front Chem.,  2019, 7, 240.
 [http://dx.doi.org/10.3389/fchem.2019.00240] [PMID:  31041306]

[94]
Franz, F.; Haschimi, B.; King, L.A.; Auwärter, V. Extraordinary long detection window of a synthetic cannabinoid metabolite in human urine – Potential impact on therapeutic decisions. Drug Test. Anal.,  2020, 12(3), 391-396.
 [http://dx.doi.org/10.1002/dta.2770] [PMID:  31944614]

[95]
 Drug Enforcement Agency. Schedules of controlled substances:	Temporary placement of 5F-EDMB-PINACA, 5F-MDMB-PICA,	FUB-AKB48, 5F-CUMYL-PINACA, and FUB-144 into schedule	I. 2019.

[96]
Mogler, L.; Franz, F.; Rentsch, D.; Angerer, V.; Weinfurtner, G.; Longworth, M.; Banister, S.D.; Kassiou, M.; Moosmann, B.; Auwärter, V. Detection of the recently emerged synthetic cannabinoid 5F-MDMB-PICA in ‘legal high’ products and human urine samples. Drug Test. Anal.,  2018, 10(1), 196-205.
 [http://dx.doi.org/10.1002/dta.2201] [PMID:  28371476]

[97]
Erol Ozturk, Y.; Yeter, O. In vitro Phase I metabolism of the recently emerged synthetic mdmb-4en-pinaca and its detection in human urine samples. J. Anal. Toxicol.,  2021, 44(9), 976-984.
 [http://dx.doi.org/10.1093/jat/bkaa017] [PMID:  32091101]

[98]
Watanabe, S.; Vikingsson, S.; Åstrand, A.; Gréen, H.; Kronstrand, R. Biotransformation of the new synthetic cannabinoid with an alkene, MDMB-4en-PINACA, by human hepatocytes, human liver microsomes, and human urine and blood. AAPS J.,  2020, 22(1), 13.
 [http://dx.doi.org/10.1208/s12248-019-0381-3] [PMID:  31848852]

[99]
Watanabe, S.; Wu, X.; Dahlen, J.; Konradsson, P.; Vikingsson, S.; Kronstrand, R.; Gréen, H. Metabolism of MMB022 and identification of dihydrodiol formation in vitro using synthesized standards. Drug Test. Anal.,  2020, 12(10), 1432-1441.
 [http://dx.doi.org/10.1002/dta.2888] [PMID:  32608533]

[100]
Dybowski, M.P.; Holowinski, P.; Typek, R.; Dawidowicz, A.L. Comprehensive analytical characteristics of N-(adamantan-1-yl)-1- (cyclohexylmethyl)-1H-indazole-3-carboxamide (ACHMINACA). Forensic Toxicol.,  2021, 39(1), 230-239.
 [http://dx.doi.org/10.1007/s11419-020-00547-6]

[101]
Leong, H.S.; Watanabe, S.; Kuzhiumparambil, U.; Fong, C.Y.; Moy, H.Y.; Yao, Y.J.; Witting, P.K.; Fu, S. Monitoring metabolism of synthetic cannabinoid 4F-MDMB-BINACA via high-resolution mass spectrometry assessed in cultured hepatoma cell line, fungus, liver microsomes and confirmed using urine samples. Forensic Toxicol.,  2021, 39(1), 198-212.
 [http://dx.doi.org/10.1007/s11419-020-00562-7]

[102]
Haschimi, B.; Mogler, L.; Halter, S.; Giorgetti, A.; Schwarze, B.; Westphal, F.; Fischmann, S.; Auwärter, V. Detection of the recently emerged synthetic cannabinoid 4F‐MDMB‐BINACA in “legal high” products and human urine specimens. Drug Test. Anal.,  2019, 11(9), 1377-1386.
 [http://dx.doi.org/10.1002/dta.2666] [PMID:  31228224]

[103]
Krotulski, A.J.; Mohr, A.L.A.; Logan, B.K. . Trend report: Q4. 2018	Synthetic cannabinoids in the United States. 2019.

[104]
Krotulski, A.J.; Mohr, A.L.A.; Logan, B.K. Trend Report: Q3 2020	Synthetic Cannabinoids in the United States (Summary), 2020.

[105]
Longworth, M.; Connor, M.; Banister, S.D.; Kassiou, M. Synthesis and pharmacological profiling of the metabolites of synthetic cannabinoid drugs APICA, STS-135, ADB-PINACA, and 5F-ADB-PINACA. ACS Chem. Neurosci.,  2017, 8(8), 1673-1680.
 [http://dx.doi.org/10.1021/acschemneuro.7b00116] [PMID:  28574245]

[106]
Alter, S.; Pulver, B.; Wilde, M.; Haschimi, B. Cumyl-CBMICA: A new synthetic cannabinoid receptor agonist containing a cyclobutyl methyl side chain. Drug Test. Anal.,  2021, 13(1), 208-216.

[107]
Körmöczi, T.; Sija, É.; Institóris, L.; Kereszty, É.M.; Ilisz, I.; Berkecz, R. Analytical methodologies for the characterization and analysis of the parent compound and phase i metabolites of 4F-MDMB-BICA in human microsome, urine and blood samples. J. Anal. Toxicol.,  2022, 46(2), 135-145.
 [http://dx.doi.org/10.1093/jat/bkab004] [PMID:  33404059]

[108]
Yue, L.; Xiang, P.; Shen, B.; Xu, D.; Song, F.; Yan, H. Metabolism of 4F‐MDMB‐BICA in zebrafish by liquid chromatography–high resolution mass spectrometry. Drug Test. Anal.,  2021, 13(6), 1223-1229.
 [http://dx.doi.org/10.1002/dta.3019] [PMID:  33629502]

[109]
 Drug Enforcement Agency.  Announcement of a Newly Identified Synthetic Cannabinoid ADB-P7AICA., 2021.
Cite As
Mini-Reviews in Medicinal Chemistry

Narrative Review of the Pharmacodynamics, Pharmacokinetics, and Toxicities of Illicit Synthetic Cannabinoid Receptor Agonists

Abstract

Graphical Abstract
