The K2/Spice Phenomenon: emergence, identification, legislation and metabolic characterization of synthetic cannabinoids in herbal incense products

References

• AAPCC (2011). Synthetic marijuana data. [Online] Available from: http://www.aapcc.org/dnn/Portals/0/Synthetic%20Marijuana%20Data%20for%20Website%2012.12.2011.pdf [last accessed 17 Dec 2011]
   Google Scholar
• AAPCC (2013). Synthetic marijuana data [Online]. Available from: https://aapcc.s3.amazonaws.com/files/library/Synthetic_Marijuana_Data_for_Website_5.31.2013.pdf [last accessed 6 Jun 2013]
   Google Scholar
• Allsop DJ, Copeland J, Norberg MM, et al. (2012). Quantifying the clinical significance of cannabis withdrawal. PLoS One 7:e44864
   PubMed Web of Science ®Google Scholar
• Ashton JC, Rahman RM, Nair SM, et al. (2007). Cerebral hypoxia-ischemia and middle cerebral artery occlusion induce expression of the cannabinoid CB2 receptor in the brain. Neurosci Lett 412:114–117
   PubMed Web of Science ®Google Scholar
• Atwood BK, Huffman J, Straiker A, Mackie, K. (2010). JWH018, a common constituent of ‘Spice' herbal blends, is a potent and efficacious cannabinoid CB receptor agonist. Br J Pharmacol 160:585–593
   PubMed Web of Science ®Google Scholar
• Atwood BK, Lee D, Straiker A, et al. (2011). CP47,497-C8 and JWH073, commonly found in ‘Spice' herbal blends, are potent and efficacious CB(1) cannabinoid receptor agonists. Eur J Pharmacol 659:139–145
   PubMed Web of Science ®Google Scholar
• Auwarter V, Dresen S, Weinmann W, et al. (2009). ‘Spice' and other herbal blends: harmless incense or cannabinoid designer drugs? J Mass Spectrom 44:832–837
   PubMed Web of Science ®Google Scholar
• Basu S, Dittel, BN. (2011). Unraveling the complexities of cannabinoid receptor 2 (CB2) immune regulation in health and disease. Immunol Res 51:26–38
   PubMed Web of Science ®Google Scholar
• Bhanushali GK, Jain G, Fatima H, et al. (2013). AKI associated with synthetic cannabinoids: a case series. Clin J Am Soc Nephrol 8:523–526
   PubMed Web of Science ®Google Scholar
• Boone, C. (2012). Teen's death officically linked to synthetic pot. The Atlanta Journal-Constitution [Online]. Available from: http://www.ajc.com/news/news/local/teens-death-officially-linked-to-synthetic-pot/nQWKk/ [last accessed 25 Sep 2012]
   Google Scholar
• Bosier B, Hermans E, Lambert, D. (2008). Differential modulation of AP-1- and CRE-driven transcription by cannabinoid agonists emphasizes functional selectivity at the CB1 receptor. Br J Pharmacol 155:24–33
   PubMed Web of Science ®Google Scholar
• Bosier B, Muccioli GG, Hermans E, Lambert, DM. (2010). Functionally selective cannabinoid receptor signalling: therapeutic implications and opportunities. Biochem Pharmacol 80:1–12
   PubMed Web of Science ®Google Scholar
• Bouaboula M, Poinot-Chazel C, Bourrie B, et al. (1995). Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1. Biochem J 312:637–641
   PubMed Web of Science ®Google Scholar
• Brents LK, Gallus-Zawada A, Radominska-Pandya A, et al. (2012). Monohydroxylated metabolites of the K2 synthetic cannabinoid JWH-073 retain intermediate to high cannabinoid 1 receptor (CB1R) affinity and exhibit neutral antagonist to partial agonist activity. Biochem Pharmacol 83:952–961
   PubMed Web of Science ®Google Scholar
• Brents LK, Reichard EE, Zimmerman SM, et al. (2011). Phase I hydroxylated metabolites of the K2 synthetic cannabinoid JWH-018 retain in vitro and in vivo cannabinoid 1 receptor affinity and activity. PLoS One 6:e21917
   PubMed Web of Science ®Google Scholar
• Brents LK, Zimmerman SM, Saffell AR, et al. (2013). Differential drug–drug interactions of the synthetic cannabinoids JWH-018 and JWH-073: implications for drug abuse and pain therapy. J Pharmacol Exp Therapeutics 346:350--361
   Google Scholar
• Brighton PJ, Marczylo TH, Rana S, et al. (2011). Characterization of the endocannabinoid system, CB(1) receptor signalling and desensitization in human myometrium. Br J Pharmacol 164:1479–1494
   PubMed Web of Science ®Google Scholar
• Bronstein AC, Spyker DA, Cantilena LR, et al. (2011). 2010 Annual report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 28th Annual Report. Clin Toxicol (Phila) 49:910–941
   PubMed Web of Science ®Google Scholar
• CBP.GOV (2009). Lab results confirm CBP in Ohio Discover Synthetic Narcotics in Incense Packets. U.S. Customs and Border Protection News Release [Online]. Available from: http://www.cbp.gov/archived/xp/cgov/newsroom/news_releases/archives/2009_news_releases/january_2009/01142009_3.xml.html [last accessed 7 Jul 2013]
   Google Scholar
• Chimalakonda KC, Bratton SM, Le VH, et al. (2011). Conjugation of Synthetic Cannabinoids, JWH-018 [Naphthalen-1-yl-(1-pentylindol-3-yl)methanone] and JWH-073 [naphthalen-1-yl-(1-butylindol-3-yl)methanone], Metabolites by Human UDP-glucuronosyltransferases. Drug Metab Dispos 39:1967–1976
   PubMed Web of Science ®Google Scholar
• Chimalakonda KC, Seely KA, Bratton SM, et al. (2012). Cytochrome p450-mediated oxidative metabolism of abused synthetic cannabinoids found in k2/spice: identification of novel cannabinoid receptor ligands. Drug Metab Dispos 40:2174–2184
   PubMed Web of Science ®Google Scholar
• Cohen J, Morrison S, Greenberg J, Saidinejad M. (2012). Clinical presentation of intoxication due to synthetic cannabinoids. Pediatrics 129:e1064–e1067
   PubMed Web of Science ®Google Scholar
• Condie R, Herring A, Koh WS, et al. (1996). Cannabinoid inhibition of adenylate cyclase-mediated signal transduction and interleukin 2 (IL-2) expression in the murine T-cell line, EL4.IL-2. J Biol Chem 271:13175–13183
   PubMed Web of Science ®Google Scholar
• Couch RA, Madhavaram H. (2012). Phenazepam and cannabinomimetics sold as herbal highs in New Zealand. Drug Test Anal 4:409–414
   PubMed Web of Science ®Google Scholar
• Crippa JA, Hallak JE, Machado-de-Sousa JP, et al. (2012). Cannabidiol for the treatment of cannabis withdrawal syndrome: a case report. J Clin Pharm Ther 38:162–164
   PubMed Web of Science ®Google Scholar
• Department of Justice (2011). Schedules of controlled substances: temporary placement of five synthetic cannabinoids into schedule I. [Online] Available from: http://www.gpo.gov:80/fdsys/pkg/FR-2011-03-01/pdf/2011-4428.pdf [last accessed 07 Dec 2012]
   Google Scholar
• Dresen S, Ferreiros N, Putz M, et al. (2010). Monitoring of herbal mixtures potentially containing synthetic cannabinoids as psychoactive compounds. J Mass Spectrom 45:1186–1194
   PubMed Web of Science ®Google Scholar
• Drugs-Forum. (2009). Snorting JWH-018. Substance information network (S.I.N.) foundation. [Online] Available from: http://www.drugs-forum.com/forum/showthread.php?t=101492 [last accessed 26 Sep 2012]
   Google Scholar
• Drugs-Forum. (2010a). JWH-018 for a non-smoker and a person with new home/insufflation. Substance Information Network (S.I.N.) Foundation. [Online] Available from: http://www.drugs-forum.com/forum/showthread.php?t=127290 [last accessed 26 Sep 2012]
   Google Scholar
• Drugs-Forum. (2010b). Experiencing the addictive properties of synthetic cannabinoids. Substance Information Network (S.I.N.) Foundation. [Online] Available from: http://www.drugs-forum.com/forum/showthread.php?t=124787 [last accessed 26 Sep 2012]
   Google Scholar
• Drugs-Forum. (2011). Am-2201 addiction…Seeking advice. Substance Information Network (S.I.N.) Foundation. [Online] Available from: http://www.drugs-forum.com/forum/showthread.php?t=168986 [last accessed 26 Sep 2012]
   Google Scholar
• Durand D, Delgado LL, de la Parra-Pellot DM, Nichols-Vinueza D. (2013). Psychosis and severe rhabdomyolysis associated with synthetic cannabinoid use. Clin Schizophr Relat Psychoses. DOI 10.3371/CSRP.DUDE.031513
   Google Scholar
• ElSohly MA, Gul W, ElSohly KM, et al. (2011). Liquid chromatography-tandem mass spectrometry analysis of urine specimens for K2 (JWH-018) metabolites. J Anal Toxicol 35:487–495
   PubMed Web of Science ®Google Scholar
• EMCDDA (2009). EMCDDA-Europol 2008 Annual Report on the implementation of Council Decision 2005/387/JHA. Lisbon. [Online] Available from: http://www.emcdda.europa.eu/attachements.cfm/att_132902_EN_2008_Implementation%20report.pdf [last accessed 7 Dec 2012]
   Google Scholar
• Englund A, Morrison PD, Nottage J, et al. (2012). Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Psychopharmacol 27:19–27
   PubMed Web of Science ®Google Scholar
• Ernst L, Kruger K, Lindigkeit R, et al. (2012). Synthetic cannabinoids in “spice-like” herbal blends: first appearance of JWH-307 and recurrence of JWH-018 on the German market. Forensic Sci Int 222:216–222
   PubMed Web of Science ®Google Scholar
• Ernst L, Schiebel HM, Theuring C, et al. (2011). Identification and characterization of JWH-122 used as new ingredient in “Spice-like” herbal incenses. Forensic Sci Int 208:e31–e35
   Google Scholar
• Every-Palmer, S. (2011). Synthetic cannabinoid JWH-018 and psychosis: An explorative study. Drug Alcohol Depend 117:152–157
   PubMed Web of Science ®Google Scholar
• Fadda P, Scherma M, Spano MS, et al. (2006). Cannabinoid self-administration increases dopamine release in the nucleus accumbens. Neuroreport 17:1629–1632
   PubMed Web of Science ®Google Scholar
• Farkas I, Kallo I, Deli L, et al. (2010). Retrograde endocannabinoid signaling reduces GABAergic synaptic transmission to gonadotropin-releasing hormone neurons. Endocrinology 151:5818–5829
   PubMed Web of Science ®Google Scholar
• Felder CC, Joyce KE, Briley EM, et al. (1995). Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol Pharmacol 48:443–450
   PubMed Web of Science ®Google Scholar
• Franklin JM, Carrasco GA. (2013). Cannabinoid receptor agonists upregulate and enhance serotonin 2A (5-HT(2A)) receptor activity via ERK1/2 signaling. Synapse 67:145–159
   PubMed Web of Science ®Google Scholar
• Franklin JM, Mathew M, Carrasco GA. (2013). Cannabinoid-induced upregulation of serotonin 2A receptors in the hypothalamic paraventricular nucleus and anxiety-like behaviors in rats. Neurosci Lett 548:165--169
   Google Scholar
• Fulp A, Bortoff K, Zhang Y, et al. (2012). Diphenyl purine derivatives as peripherally selective cannabinoid receptor 1 antagonists. J Med Chem 55:10022–10032
   PubMed Web of Science ®Google Scholar
• Galiegue S, Mary S, Marchand J, et al. (1995). Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 232:54–61
   PubMedGoogle Scholar
• Ginsburg BC, Mcmahon LR, Sanchez JJ, Javors MA. (2012). Purity of synthetic cannabinoids sold online for recreational use. J Anal Toxicol 36:66–68
   PubMed Web of Science ®Google Scholar
• Glass M, Felder CC. (1997). Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors augments cAMP accumulation in striatal neurons: Evidence for a Gs linkage to the CB1 receptor. J Neurosci 17:5327–5333
   PubMed Web of Science ®Google Scholar
• Glass M, Northup JK. (1999). Agonist selective regulation of G proteins by cannabinoid CB(1) and CB(2) receptors. Mol Pharmacol 56:1362–1369
   PubMed Web of Science ®Google Scholar
• Goldschmidt L, Richardson GA, Willford JA, et al. (2012). School achievement in 14-year-old youths prenatally exposed to marijuana. Neurotoxicol Teratol 34:161–167
   PubMed Web of Science ®Google Scholar
• Gonzalez R, Schuster RM, Mermelstein RJ, et al. (2012). Performance of young adult cannabis users on neurocognitive measures of impulsive behavior and their relationship to symptoms of cannabis use disorders. J Clin Exp Neuropsychol 34:962–976
   PubMed Web of Science ®Google Scholar
• Gottardo R, Chiarini A, Dal Pra I, et al. (2012). Direct screening of herbal blends for new synthetic cannabinoids by MALDI-TOF MS. J Mass Spectrom 47:141–146
   PubMed Web of Science ®Google Scholar
• Goupil E, Laporte SA, Hebert TE. (2012). Functional selectivity in GPCR signaling: understanding the full spectrum of receptor conformations. Mini Rev Med Chem 12:817–830
   PubMed Web of Science ®Google Scholar
• Grabenauer M, Krol WL, Wiley JL, Thomas BF. (2012). Analysis of synthetic cannabinoids using high-resolution mass spectrometry and mass defect filtering: implications for nontargeted screening of designer drugs. Anal Chem 84:5574–5581
   PubMed Web of Science ®Google Scholar
• Grant JE, Chamberlain SR, Schreiber L, Odlaug BL. (2012). Neuropsychological deficits associated with cannabis use in young adults. Drug Alcohol Depend 121:159–162
   PubMed Web of Science ®Google Scholar
• Griffiths P, Sedefov R, Gallegos A, Lopez D. (2010). How globalization and market innovation challenge how we think about and respond to drug use: ‘Spice' a case study. Addiction 105:951–953
   PubMed Web of Science ®Google Scholar
• Grotenhermen F, Muller-Vahl K. (2012). The therapeutic potential of cannabis and cannabinoids. Dtsch Arztebl Int 109:495–501
   PubMed Web of Science ®Google Scholar
• GW Pharmaceuticals (2012a). Third phase III Sativex cancer pain trial commences [Online]. Available from: http://www.gwpharm.com/Third%20phase%20III%20Sativex%20cancer%20pain%20trial%20commences.aspx [last accessed 06 Dec 2012]
   Google Scholar
• GW Pharmaceuticals (2012b). Package leaflet: Information for the patient, Sativex Oromucosal Spray [Online] Available from: www.medicines.org.uk/EMC/pdfviewer.aspx?isAttachment=true&documentid=23228 [last accessed 06 Dec 2012]
   Google Scholar
• Habayeb OM, Taylor AH, Bell SC, et al. (2008). Expression of the endocannabinoid system in human first trimester placenta and its role in trophoblast proliferation. Endocrinology 149:5052–5060
   PubMed Web of Science ®Google Scholar
• Harris CR, Brown, A. (2012). Synthetic cannabinoid intoxication: a case series and review. J Emerg Med 44:360–366
   PubMed Web of Science ®Google Scholar
• Hermanns-Clausen M, Kneisel S, Szabo B, Auwarter V. (2012). Acute toxicity due to the confirmed consumption of synthetic cannabinoids: Clinical and laboratory findings. Addiction 108:534–544
   PubMed Web of Science ®Google Scholar
• Hill AJ, Weston SE, Jones NA, et al. (2010). Delta-Tetrahydrocannabivarin suppresses in vitro epileptiform and in vivo seizure activity in adult rats. Epilepsia 51:1522–1532
   PubMed Web of Science ®Google Scholar
• Horne AW, Phillips JA, 3rd, Kane N, et al. (2008). CB1 expression is attenuated in Fallopian tube and decidua of women with ectopic pregnancy. PLoS One 3:e3969
   PubMed Web of Science ®Google Scholar
• Hu X, Primack BA, Barnett TE, Cook RL. (2011). College students and use of K2: an emerging drug of abuse in young persons. Subst Abuse Treat Prev Policy 6:16--20
   PubMed Web of Science ®Google Scholar
• Huang CC, Lo SW, Hsu KS. (2001). Presynaptic mechanisms underlying cannabinoid inhibition of excitatory synaptic transmission in rat striatal neurons. J Physiol 532:731–748
   PubMed Web of Science ®Google Scholar
• Hudson S, Ramsey J, King L, et al. (2010). Use of high-resolution accurate mass spectrometry to detect reported and previously unreported cannabinomimetics in “herbal high” products. J Anal Toxicol 34:252–260
   PubMed Web of Science ®Google Scholar
• Jin MJ, Lee J, In MK, Yoo HH. (2012). Characterization of in vitro metabolites of cp 47,497, a synthetic cannabinoid, in human liver microsomes by LC-MS/MS. J Forensic Sci 58:195–199
   PubMed Web of Science ®Google Scholar
• Jinwala FN, Gupta M. (2012). Synthetic cannabis and respiratory depression. J Child Adolesc Psychopharmacol 22:459–462
   PubMed Web of Science ®Google Scholar
• Johnston LD, Malley PM, Bachman JG, Schulenberg JE. (2011). Marijuana use continues to rise among U.S. teens, while alcohol use hits historic lows. [Online] Available from: http://www.monitoringthefuture.org [last accessed 16 Dec 2011]
   Google Scholar
• Kneisel S, Westphal F, Bisel P, et al. (2012). Identification and structural characterization of the synthetic cannabinoid 3-(1-adamantoyl)-1-pentylindole as an additive in ‘herbal incense'. J Mass Spectrom 47:195–200
   PubMed Web of Science ®Google Scholar
• Kovacs FE, Knop T, Urbanski MJ, et al. (2012). Exogenous and endogenous cannabinoids suppress inhibitory neurotransmission in the human neocortex. Neuropsychopharmacology 37:1104–1114
   PubMed Web of Science ®Google Scholar
• Kunos G, Tam, J. (2011). The case for peripheral CB(1) receptor blockade in the treatment of visceral obesity and its cardiometabolic complications. Br J Pharmacol 163:1423–1431
   PubMed Web of Science ®Google Scholar
• Lauckner JE, Hille B, Mackie, K. (2005). The cannabinoid agonist WIN55,212-2 increases intracellular calcium via CB1 receptor coupling to Gq/11 G proteins. Proc Natl Acad Sci U S A 102:19144–19149
   PubMed Web of Science ®Google Scholar
• Leweke FM, Piomelli D, Pahlisch F, et al. (2012). Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry 2:e94
   PubMed Web of Science ®Google Scholar
• Lewis SE, Paro R, Borriello L, et al. (2012). Long-term use of HU210 adversely affects spermatogenesis in rats by modulating the endocannabinoid system. Int J Androl 35:731–740
   PubMed Web of Science ®Google Scholar
• Ligresti A, Moriello AS, Starowicz K, et al. (2006). Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther 318:1375–1387
   PubMed Web of Science ®Google Scholar
• Lindigkeit R, Boehme A, Eiserloh I, et al. (2009). Spice: a never ending story? Forensic Sci Int 191:58–63
   PubMed Web of Science ®Google Scholar
• Liu X, Jutooru I, Lei P, et al. (2012). Betulinic acid targets YY1 and ErbB2 through cannabinoid receptor-dependent disruption of microRNA-27a:ZBTB10 in breast cancer. Mol Cancer Ther 11:1421–1431
   PubMed Web of Science ®Google Scholar
• Lodish H, Berk A, Kaiser CA, et al. (2012). Molecular cell biology, 7th ed. New York: W.H. Freeman
   Google Scholar
• Lombard C, Nagarkatti M, Nagarkatti, P. (2007). CB2 cannabinoid receptor agonist, JWH-015, triggers apoptosis in immune cells: Potential role for CB2-selective ligands as immunosuppressive agents. Clin Immunol 122:259–270
   PubMed Web of Science ®Google Scholar
• Lou ZY, Chen C, He Q, et al. (2011). Targeting CB(2) receptor as a neuroinflammatory modulator in experimental autoimmune encephalomyelitis. Mol Immunol 49:453–461
   PubMed Web of Science ®Google Scholar
• Mackie K. (2005). Cannabinoid receptor homo- and heterodimerization. Life Sci 77:1667–1673
   PubMed Web of Science ®Google Scholar
• Mackie K, Lai Y, Westenbroek R, Mitchell R. (1995). Cannabinoids activate an inwardly rectifying potassium conductance and inhibit Q-type calcium currents in AtT20 cells transfected with rat brain cannabinoid receptor. J Neurosci 15:6552–6561
   PubMed Web of Science ®Google Scholar
• Maneuf YP, Brotchie JM. (1997). Paradoxical action of the cannabinoid WIN 55,212-2 in stimulated and basal cyclic AMP accumulation in rat globus pallidus slices. Br J Pharmacol 120:1397–1398
   PubMed Web of Science ®Google Scholar
• Martin-Moreno AM, Brera B, Spuch C, et al. (2012). Prolonged oral cannabinoid administration prevents neuroinflammation, lowers beta-amyloid levels and improves cognitive performance in Tg APP 2576 mice. J Neuroinflammation 9:8
   PubMed Web of Science ®Google Scholar
• Maurer HH, Sauer C, Theobald DS. (2006). Toxicokinetics of drugs of abuse: current knowledge of the isoenzymes involved in the human metabolism of tetrahydrocannabinol, cocaine, heroin, morphine, and codeine. Ther Drug Monit 28:447–453
   PubMed Web of Science ®Google Scholar
• Mayo N. (2011). Coroner: Lamar Jack ingested chemical found in fake marijuana before he died. Anderson Independent Mail [Online]. Available from: http://www.independentmail.com/news/2011/oct/15/coroner-lamar-jack-ingested-chemical-found-fake-ma/ [last accessed 6 Dec 2012]
   Google Scholar
• Mcallister SD, Griffin G, Satin LS, Abood ME. (1999). Cannabinoid receptors can activate and inhibit G protein-coupled inwardly rectifying potassium channels in a xenopus oocyte expression system. J Pharmacol Exp Ther 291:618–626
   PubMed Web of Science ®Google Scholar
• Mcintosh BT, Hudson B, Yegorova S, et al. (2007). Agonist-dependent cannabinoid receptor signalling in human trabecular meshwork cells. Br J Pharmacol 152:1111–1120
   PubMed Web of Science ®Google Scholar
• Mcquade D, Hudson S, Dargan PI, Wood DM. (2012). First European case of convulsions related to analytically confirmed use of the synthetic cannabinoid receptor agonist AM-2201. Eur J Clin Pharmacol 69:373–376
   PubMed Web of Science ®Google Scholar
• Mechoulam R, Parker LA. (2012). The endocannabinoid system and the brain. Annu Rev Psychol 64:21–47
   PubMed Web of Science ®Google Scholar
• Meier MH, Caspi A, Ambler A, et al. (2012). Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci U S A 109:E2657–E2664
   PubMed Web of Science ®Google Scholar
• Merola G, Aturki Z, D'orazio G, et al. (2012). Analysis of synthetic cannabinoids in herbal blends by means of nano-liquid chromatography. J Pharm Biomed Anal 71:45–53
   PubMed Web of Science ®Google Scholar
• Mir A, Obafemi A, Young A, Kane, C. (2011). Myocardial infarction associated with use of the synthetic cannabinoid K2. Pediatrics 128:e1622–e1627
   PubMed Web of Science ®Google Scholar
• Moller I, Wintermeyer A, Bender K, et al. (2011). Screening for the synthetic cannabinoid JWH-018 and its major metabolites in human doping controls. Drug Test Anal 3:609–620
   PubMed Web of Science ®Google Scholar
• Montgomery C, Seddon AL, Fisk JE, et al. (2012). Cannabis-related deficits in real-world memory. Hum Psychopharmacol 27:217–225
   PubMed Web of Science ®Google Scholar
• Moran CL, Le VH, Chimalakonda KC, et al. (2011). Quantitative measurement of JWH-018 and JWH-073 metabolites excreted in human urine. Anal Chem 83:4228–4236
   PubMed Web of Science ®Google Scholar
• Morrison PD, Zois V, McKeown DA, et al. (2009). The acute effects of synthetic intravenous Delta9-tetrahydrocannabinol on psychosis, mood and cognitive functioning. Psychol Med 39:1607–1616
   PubMed Web of Science ®Google Scholar
• Musah RA, Domin MA, Cody RB, et al. (2012). Direct analysis in real time mass spectrometry with collision-induced dissociation for structural analysis of synthetic cannabinoids. Rapid Commun Mass Spectrom 26:2335–2342
   PubMed Web of Science ®Google Scholar
• Musshoff F, Madea B, Kernbach-Wighton G, et al. (2013). Driving under the influence of synthetic cannabinoids (“Spice”): a case series. Int J Legal Med DOI 10.1007/s00414-013-0864-1
   Google Scholar
• National Conference of State Legislatures (2012). Synthetic CAnnabinoids (a.k.a. “K2/”Spice) enactments [Online]. Available from: http://www.ncsl.org/issues-research/justice/synthetic-cannabinoids-enactments.aspx [last accessed 11 Oct 2012]
   Google Scholar
• Office of Diversion Control (2009). National Forensic Laboratory Information System: Year 2008 annual report. Washington, DC: U.S. Drug Enforcement Administration. [Online] Available from: www.deadiversion.usdoj.gov/nflis/2008annual_rpt.pdf [last accessed 7 Dec 2012]
   Google Scholar
• Office of Diversion Control (2011). Special report: synthetic cannabinoids and synthetic cathinones reported in National Forensic Laboratory Information System, 2009–2010. Springfield (VA): U.S. Drug Enforcement Administration. [Online] Available from: www.deadiversion.usdoj.gov/nflis/2010rx_synth.pdf [last accessed 7 Dec 2012]
   Google Scholar
• Office of Diversion Control (2012). National Forensic Laboratory Information System: Midyear report 2011. Springfield (VA): U.S. Drug Enforcement Administration. [Online] Available from: http://www.deadiversion.usdoj.gov/nflis/2011midyear.pdf [last accessed 7 Dec 2012]
   Google Scholar
• Patton AC, Moran C, McCain K, et al. (2013). K2 toxicity: Fatal case of psychiatric complications following AM2201 exposure. J Forensic Sci DOI 10.1111/1556-4029.12216
   Google Scholar
• Pertwee RG. (2008). The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol 153:199–215
   PubMed Web of Science ®Google Scholar
• Pertwee RG, Howlett AC, Abood ME, et al. (2010). International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: Beyond CB and CB. Pharmacol Rev 62:588–631
   PubMed Web of Science ®Google Scholar
• Price DA, Martinez AA, Seillier A, et al. (2009). WIN55,212-2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Eur J Neurosci 29:2177–2186
   PubMed Web of Science ®Google Scholar
• Psychoyos D, Vinod KY, Cao J, et al. (2012). Cannabinoid receptor 1 signaling in embryo neurodevelopment. Birth Defects Res B Dev Reprod Toxicol 95:137–150
   PubMed Web of Science ®Google Scholar
• Psychonaut Web Mapping Research Group (2009). Spice report. [Online] Available from: http://www.psychonautproject.eu/documents/reports/Spice.pdf [last accessed 07 Dec 2012]
   Google Scholar
• Psychoyos D, Vinod KY. (2012). Marijuana, spice ‘herbal high', and early neural development: implications for rescheduling and legalization. Drug Test Anal 5:27–45
   PubMed Web of Science ®Google Scholar
• Rajasekaran M, Brents LK, Franks LN, et al. (2013). Human metabolites of synthetic cannabinoids JWH-018 and JWH-073 bind with high affinity and act as potent agonists at cannabinoid type-2 receptors. Toxicol Appl Pharmacol 269:100–108
   PubMed Web of Science ®Google Scholar
• Regard JBS, Coughlin SR. (2008a) Anatomical profiling of CB1R expression [Online]. Available from: http://pdsp.med.unc.edu/ShaunCell/webfiles/Cnr1%20graph%201.jpg.800.jpg [last accessed 18 Jul 2013]
   Google Scholar
• Regard JBS, Coughlin, S.R. (2008b) Antomical profiling of CB2R expression [Online]. Available from: http://pdsp.med.unc.edu/ShaunCell/webfiles/Cnr2%20graph%201.jpg.800.jpg [last accessed 18 Jul 2013]
   Google Scholar
• Riedel G, Fadda P, McKillop-Smith S, et al. (2009). Synthetic and plant-derived cannabinoid receptor antagonists show hypophagic properties in fasted and non-fasted mice. Br J Pharmacol 156:1154–1166
   PubMed Web of Science ®Google Scholar
• Rivera P, Luque-Rojas MJ, Pastor A, et al. (2012). Diet-dependent modulation of hippocampal expression of endocannabinoid signaling-related proteins in cannabinoid antagonist-treated obese rats. Eur J Neurosci 37:105–117
   PubMed Web of Science ®Google Scholar
• Russo EB. (2011). Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol 163:1344–1364
   PubMed Web of Science ®Google Scholar
• Sanchez Robles EM, Bagues Arias A, Martin Fontelles MI. (2012). Cannabinoids and muscular pain: Effectiveness of the local administration in rat. Eur J Pain 16:1116–1127
   PubMed Web of Science ®Google Scholar
• Savini D. (2011). 2 Investigators: Synthetic marijuana product blamed in teen's deadly crash. CBS Chicago [Online]. Available from: http://chicago.cbslocal.com/2011/07/07/2-investigators-synthetic-marijuana-product-blamed-in-teens-deadly-crash/ [last accessed 06 Dec 2012]
   Google Scholar
• Schecter A, Brian R. (2011). Retailers selling legal high “Time Bombs” to kids, doctor says. ABC News [Online]. Available from: http://abcnews.go.com/Blotter/retailers-selling-legal-high-time-bombs-kids-doctor/story?id=13753898 [last accessed 25 Sep 2012]
   Google Scholar
• Schubart CD, Sommer IE, van Gastel WA, et al. (2011). Cannabis with high cannabidiol content is associated with fewer psychotic experiences. Schizophr Res 130:216–221
   PubMed Web of Science ®Google Scholar
• Seely KA, Lapoint J, Moran JH, Fattore L. (2012). Spice drugs are more than harmless herbal blends: a review of the pharmacology and toxicology of synthetic cannabinoids. Prog Neuropsychopharmacol Biol Psychiatry 39:234–243
   PubMed Web of Science ®Google Scholar
• Sekula K, Zuba D, Stanaszek, R. (2012). Identification of naphthoylindoles acting on cannabinoid receptors based on their fragmentation patterns under ESI-QTOFMS. J Mass Spectrom 47:632–643
   PubMed Web of Science ®Google Scholar
• Shim JY, Bertalovitz AC, Kendall, D. A. (2012). Probing the Interaction of SR141716A with the CB1 Receptor. J Biol Chem 287:38741–38754
   PubMed Web of Science ®Google Scholar
• Shoemaker JL, Ruckle MB, Mayeux PR, Prather, P. L. (2005). Agonist-directed trafficking of response by endocannabinoids acting at CB2 receptors. J Pharmacol Exp Ther 315:828–838
   PubMed Web of Science ®Google Scholar
• Shoemaker JL, Seely KA, Reed RL, et al. (2007). The CB2 cannabinoid agonist AM-1241 prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis when initiated at symptom onset. J Neurochem 101:87–98
   PubMed Web of Science ®Google Scholar
• Singh UP, Singh NP, Singh B, et al. (2012). Cannabinoid receptor-2 (CB2) agonist ameliorates colitis in IL-10(−/−) mice by attenuating the activation of T cells and promoting their apoptosis. Toxicol Appl Pharmacol 258:256–267
   PubMed Web of Science ®Google Scholar
• Sobolevsky T, Prasolov I, Rodchenkov G. (2010). Detection of JWH-018 metabolites in smoking mixture post-administration urine. Forensic Sci Int 200:141–147
   PubMed Web of Science ®Google Scholar
• Sobolevsky T, Prasolov I, Rodchenkov G. (2012). Detection of urinary metabolites of AM-2201 and UR-144, two novel synthetic cannabinoids. Drug Test Anal DOI 10.1002/dta.1418
   Google Scholar
• Steup C. (2008). Untersuchung des handelsproduktes “Spice” (Investigation of the commercial product “Spice”). Frankfurt, Germany: THC Pharm GmbH [Online] Available from: http://usualredant.de/downloads/analyse-thc-pharm-spice-jwh-018.pdf [last accessed 07 Dec 2012]
   Google Scholar
• Straiker A, Mackie K. (2005). Depolarization-induced suppression of excitation in murine autaptic hippocampal neurones. J Physiol 569:501–517
   PubMed Web of Science ®Google Scholar
• Sun X, Dey SK. (2012). Endocannabinoid signaling in female reproduction. ACS Chem Neurosci 3:349–355
   PubMed Web of Science ®Google Scholar
• Surugiu ME, Minca DG. (2012). European dimension of cannabinoid-like products use. J Med Life 5:79–81
   PubMedGoogle Scholar
• Szabo B, Siemes S, Wallmichrath I. (2002). Inhibition of GABAergic neurotransmission in the ventral tegmental area by cannabinoids. Eur J Neurosci 15:2057–2061
   PubMed Web of Science ®Google Scholar
• Taffe MA. (2012). Delta(9) tetrahydrocannabinol impairs visuo-spatial associative learning and spatial working memory in rhesus macaques. J Psychopharmacol 26:1299–1306
   PubMed Web of Science ®Google Scholar
• Thalji J. (2012). Use of synthetic marijuana linked to drowning death of Clearwater teen. Tampa Bay Times [Online]. Available from: http://www.tampabay.com/news/publicsafety/use-of-synthetic-marijuana-linked-to-drowning-death-of-clearwater-teen/1223770 [last accessed 25 Sep 2012]
   Google Scholar
• Tofighi B, Lee JD. (2012). Internet highs – Seizures after consumption of synthetic cannabinoids purchased online. J Addict Med 6:240–241
   PubMed Web of Science ®Google Scholar
• Tung CK, Chiang TP, Lam M. (2012). Acute mental disturbance caused by synthetic cannabinoid: a potential emerging substance of abuse in Hong Kong. East Asian Arch Psychiatry 22:31–33
   PubMedGoogle Scholar
• Uchiyama N, Kikura-Hanajiri R, Ogata J, Goda Y. (2010). Chemical analysis of synthetic cannabinoids as designer drugs in herbal products. Forensic Sci Int 198:31–38
   PubMed Web of Science ®Google Scholar
• Unimed Pharmaceuticals (2004). Marinol (Dronabinol) new drug application. FDA [Online] Available from: http://www.fda.gov/ohrms/dockets/dockets/05n0479/05N-0479-emc0004-04.pdf [last accessed 02 Jan 2013]
   Google Scholar
• United States 21 U.S.C. § 813 (1986) Treatment of controlled substance analogues. U.S. Government Printing Office. pp. 452 [Online]. Available from: http://www.gpo.gov:80/fdsys/pkg/USCODE-2008-title21/pdf/USCODE-2008-title21-chap13-subchapI-partB-sec813.pdf [last accessed 01 Jan 2013]
   Google Scholar
• United States (2012). Synthetic drug abuse prevention act of 2012. U.S. Government Printing Office. pp. 138-140. [Online] Available from: http://www.gpo.gov/fdsys/pkg/BILLS-112s3187enr/pdf/BILLS-112s3187enr.pdf [last accessed 7 Dec 2013]
   Google Scholar
• Valdeolivas S, Satta V, Pertwee RG, et al. (2012). Sativex-like combination of phytocannabinoids is neuroprotective in malonate-lesioned rats, an inflammatory model of Huntington's disease: Role of CB(1) and CB(2) receptors. ACS Chem Neurosci 3:400–406
   PubMed Web of Science ®Google Scholar
• Valoti E, Casagni E, Dell'Acqua L, et al. (2012). Identification of 1-butyl-3-(1-(4-methyl)naphtoyl)indole detected for the first time in “herbal high” products on the Italian market. Forensic Sci Int 223:e42–e46
   Google Scholar
• Vandrey R, Dunn KE, Fry JA, Girling ER. (2011). A survey study to characterize use of Spice products (synthetic cannabinoids). Drug Alcohol Depend 120:238–241
   PubMed Web of Science ®Google Scholar
• Vardakou I, Pistos C, Spiliopoulou, C. (2010). Spice drugs as a new trend: mode of action, identification and legislation. Toxicol Lett 197:157–162
   PubMed Web of Science ®Google Scholar
• Vidinsky B, Gal P, Pilatova M, Vidova Z, et al. (2012). Anti-proliferative and anti-angiogenic effects of CB2R agonist (JWH-133) in non-small lung cancer cells (A549) and human umbilical vein endothelial cells: an in vitro investigation. Folia Biol (Praha) 58:75–80
   PubMed Web of Science ®Google Scholar
• Walter L, Franklin A, Witting A, et al. (2003). Nonpsychotropic cannabinoid receptors regulate microglial cell migration. J Neurosci 23:1398–1405
   PubMed Web of Science ®Google Scholar
• Westphal F, Sonnichsen FD, Thiemt, S. (2012). Identification of 1-butyl-3-(1-(4-methyl)naphthoyl)indole in a herbal mixture. Forensic Sci Int 215:8–13
   PubMed Web of Science ®Google Scholar
• Wintermeyer A, Moller I, Thevis M, et al. (2010). In vitro phase I metabolism of the synthetic cannabimimetic JWH-018. Anal Bioanal Chem 398:2141–2153
   PubMed Web of Science ®Google Scholar
• World Health Organization (2012). Management of substance abuse [Online]. Available: http://www.who.int/substance_abuse/facts/cannabis/en/ [last accessed 02 Jan 2013]
   Google Scholar
• Zarruk JG, Fernandez-Lopez D, Garcia-Yebenes I, et al. (2012). Cannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophage/microglial activation concomitant to neuroprotection. Stroke 43:211–219
   PubMed Web of Science ®Google Scholar
• Zhang Q, Ma P, Cole RB, Wang G. (2006). Identification of in vitro metabolites of JWH-015, an aminoalkylindole agonist for the peripheral cannabinoid receptor (CB2) by HPLC-MS/MS. Anal Bioanal Chem 386:1345–1355
   PubMed Web of Science ®Google Scholar
• Zhang Q, Ma P, Iszard M, et al. (2002). In vitro metabolism of R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo [1,2,3-de]1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate, a cannabinoid receptor agonist. Drug Metab Dispos 30:1077–1086
   PubMed Web of Science ®Google Scholar
• Zimmermann US, Winkelmann PR, Pilhatsch M, et al. (2009). Withdrawal phenomena and dependence syndrome after the consumption of “spice gold”. Dtsch Arztebl Int 106:464–467
   PubMed Web of Science ®Google Scholar
• Zuardi AW. (2006). History of cannabis as a medicine: a review. Rev Bras Psiquiatr 28:153–157
   PubMed Web of Science ®Google Scholar
• Zuba D, Byrska B, Maciow M. (2011). Comparison of “herbal highs” composition. Anal Bioanal Chem 400:119–126
   PubMed Web of Science ®Google Scholar