Synthetic cathinone and cannabinoid designer drugs pose a major risk for public health

Frontiers in Psychiatry

Volumn 8, Issue AUG, 2017, Pages

  Weinstein, Aviv M ^a   Rosca, Paola ^b   Fattore, Liana ^c   London, Edythe D ^d,e  

^a ARIEL UNIVERSITY   (Israel)

^b MINISTRY OF HEALTH   (Israel)

^c CNR   (Italy)

^d UNIVERSITY OF CALIFORNIA   (United States)

^e UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Amphetamine; Cannabis; Cathinones; New psychoactive drugs; Synthetic drugs

Indexed keywords

EID: 85028305805     PISSN: None     EISSN: 16640640     Source Type: Journal    
DOI: 10.3389/fpsyt.2017.00156     Document Type: Article

References (152)

1. Baumann MH, Solis E Jr, Watterson LR, Marusich JA, Fantegrossi WE, Wiley JL. Baths salts, spice, and related designer drugs: the science behind the headlines. J Neurosci (2014) 34(46):15150-8. doi:10.1523/JNEUROSCI. 3223-14.2014
2. Papaseit E, Farré M, Schifano F, Torrens M. Emerging drugs in Europe. Curr Opin Psychiatry (2014) 27(4):243-50. doi:10.1097/YCO. 0000000000000071
3. Zawilska JB, Wojcieszak J. Designer cathinones-an emerging class of novel recreational drugs. Forensic Sci Int (2013) 231(1-3):42-53. doi:10.1016/j. forsciint.2013.04.015
4. Zawilska JB. Mephedrone and other cathinones. Curr Opin Psychiatry (2014) 27(4):256-62. doi:10.1097/YCO.0000000000000066
5. Zawilska J. "Legal highs"-an emerging epidemic of novel psychoactive substances. Int Rev Neurobiol (2015) 120:273-300. doi:10.1016/bs.irn. 2015.02.009
6. Cottencin O, Rolland B, Karila L. New designer drugs (synthetic cannabinoids and synthetic cathinones): review of literature. Curr Pharm Des (2014) 20(25):4106-11. doi:10.2174/13816128113199990622
7. German CL, Fleckenstein AE, Hanson GR. Bath salts and synthetic cathinones: an emerging designer drug phenomenon. Life Sci (2014) 97(1):2-8. doi:10.1016/j.lfs.2013.07.023
8. Spiller HA, Ryan ML, Weston RG, Jansen J. Clinical experience with and analytical confirmation of "bath salts" and "legal highs" (synthetic cathinones) in the United States. Clin Toxicol (2011) 49(6):499-505. doi:10.3109/155636 50.2011.590812
9. United Nations Office on Drugs and Crime (UNODC). World Drug Report. New York: United Nations Publication (2015). Sales No. E.15.XI.
10. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). New Psychoactive Substances in Europe (2015). An Update from the EU Early Warning System. Luxembourg: Publications Office of the European Union (2015).
11. Law R, Schier J, Martin C, Chang A, Wolkin A; Centers for Disease. Notes from the field: increase in reported adverse health effects related to synthetic cannabinoid use-United States, January-May 2015. MMWR Morb Mortal Wkly Rep (2015) 64(22):618-9.
12. Vandrey R, Johnson MW, Johnson PS, Khalil MA. Novel drugs of abuse: a snapshot of an evolving marketplace. Adolesc Psychiatry (2013) 3(2):123-34. doi:10.2174/2210676611303020003
13. United Nations Office on Drugs and Crime (UNODOC). World Drug Report. New York: United Nations Publication (2016). Sales No. E.16.XI.7.
14. De Luca MA, Bimpisidis Z, Melis M, Marti M, Caboni P, Valentini V, et al. Stimulation of in vivo dopamine transmission and intravenous self-administration in rats and mice by JWH-018, a spice cannabinoid. Neuropharmacology (2015) 99:705-14. doi:10.1016/j.neuropharm.2015. 08.041
15. Miliano C, Serpelloni G, Rimondo C, Mereu M, Marti M, De Luca MA. Neuropharmacology of new psychoactive substances (NPS): focus on the rewarding and reinforcing properties of cannabimimetics and amphetamine-like stimulants. Front Neurosci (2016) 10:153. doi:10.3389/fnins. 2016.00153
16. Baumann MH, Volkow ND. Abuse of new psychoactive substances (NPS): threats and solutions. Neuropsychopharmacology (2016) 41(3):663-5. doi:10.1038/npp.2015.260
17. Baumann MH, Ayestas MA Jr, Partilla JS, Sink JR, Shulgin AT, Daley PF, et al. The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue. Neuropsychopharmacology (2012) 37:1192-203. doi:10.1038/npp.2011.304
18. Emerson TS, Cisek JE. Methcathinone: a Russian designer amphetamine infiltrates the rural midwest. Ann Emerg Med (1993) 22:1897-903. doi:10.1016/S0196-0644(05)80419-6
19. Karch SB. Cathinone neurotoxicity (the "3Ms"). Curr Neuropharmacol (2015) 13(1):21-5. doi:10.2174/1570159X13666141210225009
20. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Thematic Paper-Understanding the 'Spice' Phenomenon. Luxembourg: Office for Official Publications of the European Communities (2009).
21. Macher R, Burke TW, Owen SS. Synthetic Marijuana. FBI Law Enforcement Bulletin. (2012). Available from: http://leb.fbi.gov/2012/may/ synthetic-marijuana
22. Mills B, Yepes A, Nugent K. Synthetic cannabinoids. Am J Med Sci (2015) 350(1):59-62. doi:10.1097/MAJ.0000000000000466
23. Seely K, Lapoint J, Moran JH, Fattore L. Spice drugs are more than harmless herbal blends: a review of the pharmacology and toxicology of synthetic cannabinoids. Prog Neuropsychopharmacol Biol Psychiatry (2012) 39(2):234-43. doi:10.1016/j.pnpbp.2012.04.017
24. Makriyannis A, Deng H. Cannabimimetic Indole Derivates. United States patent US 20080090871A (2007).
25. Nakajima M, al'Absi M, Dokam A, Alsoofi M, Khalil NS, Al Habori M. Gender differences in patterns and correlates of khat and tobacco use. Nicotine Tob Res (2013) 15(6):1130-5. doi:10.1093/ntr/nts257
26. Stevenson M, Fitzgerald J, Banwell C. Chewing as a social act: cultural displacement and khat consumption in the East African communities of Melbourne. Drug Alcohol Rev (1996) 15(1):73-82. doi:10.1080/09595239600185691
27. Johnson S, Johnson MW. Investigation of "bath salts" use patterns within an online sample of users in the United States. J Psychoactive Drugs (2014) 46(5):369-78. doi:10.1080/02791072.2014.962717
28. Péterfi A, Tarján A, Horváth GC, Csesztregi T, Nyírády A. Changes in patterns of injecting drug use in Hungary: a shift to synthetic cathinones. Drug Test Anal (2014) 6(7-8):825-31. doi:10.1002/dta.1625
29. Dargan PI, Albert S, Wood DM. Mephedrone use and associated adverse effects in school and college/university students before the UK legislation change. QJM (2010) 103(11):875-9. doi:10.1093/qjmed/hcq134
30. Sande M. Characteristics of the use of 3-MMC and other new psychoactive drugs in Slovenia and the perceived problems experienced by users. Int J Drug Policy (2016) 27:65-73. doi:10.1016/j.drugpo.2015.03.005
31. Helander A, Bäckberg M, Hultén P, Al-Saffar Y, Beck O. Detection of new psychoactive substance use among emergency room patients: results from the Swedish STRIDA project. Forensic Sci Int (2014) 243:23-9. doi:10.1016/j. forsciint.2014.02.022
32. Gunderson EW, Haughey HM, Ait-Daoud N, Joshi AS, Hart CL. "Spice" and "K2" herbal highs: a case series and systematic review of the clinical effects and biopsychosocial implications of synthetic cannabinoid use in humans. Am J Addict (2012) 21(4):320-6. doi:10.1111/j.1521-0391.2012. 00240.x
33. Vidourek RA, King KA, Burbage ML. Reasons for synthetic THC use among college students. J Drug Educ (2013) 43(4):353-63. doi:10.2190/DE.43.4.d
34. Castellanos D, Thornton G. Synthetic cannabinoid use: recognition and management. J Psychiatr Pract (2012) 18(2):86-93. doi:10.1097/01. pra.0000413274.09305.9c
35. Hu X, Primack BA, Barnett TE, Cook RL. College students and use of K2: an emerging drug of abuse in young persons. Subst Abuse Treat Prev Policy (2011) 6:16. doi:10.1186/1747-597X-6-16
36. Gutierrez KM, Cooper TV. Investigating correlates of synthetic marijuana and Salvia use in light and intermittent smokers and college students in a predominantly Hispanic sample. Exp Clin Psychopharmacol (2014) 22(6):524-9. doi:10.1037/a0038014
37. Caviness CM, Tzilos G, Anderson BJ, Stein MD. Synthetic cannabinoids: use and predictors in a community sample of young adults. Subst Abus (2015) 36(3):368-73. doi:10.1080/08897077.2014.959151
38. Egan KL, Suerken CK, Reboussin BA, Spangler J, Wagoner KG, Sutfin EL, et al. K2 and spice use among a cohort of college students in southeast region of the USA. Am J Drug Alcohol Abuse (2015) 1:1-6. doi:10.3109/00 952990.2015.1043438
39. Palamar JJ, Acosta P. Synthetic cannabinoid use in a nationally representative sample of US high school seniors. Drug Alcohol Depend (2015) 149:194-202. doi:10.1016/j.drugalcdep.2015.01.044
40. Bonar EE, Ashrafioun L, Ilgen MA. Synthetic cannabinoid use among patients in residential substance use disorder treatment: prevalence, motives, and correlates. Drug Alcohol Depend (2014) 143:268-71. doi:10.1016/j. drugalcdep.2014.07.009
41. Palamar JJ, Martins SS, Su MK, Ompad DC. Self-reported use of novel psychoactive substances in a US nationally representative survey: prevalence, correlates, and a call for new survey methods to prevent underre porting. Drug Alcohol Depend (2015) 156:112-9. doi:10.1016/j.drugalcdep. 2015.08.028
42. Winstock AR, Barratt MJ. Synthetic cannabis: a comparison of patterns of use and effect profile with natural cannabis in a large global sample. Drug Alcohol Depend (2013) 131(1-2):106-11. doi:10.1016/j.drugalcdep. 2012.12.011
43. Winstock A, Lynskey M, Borschmann R, Waldron J. Risk of emergency medical treatment following consumption of cannabis or synthetic cannabinoids in a large global sample. J Psychopharmacol (2015) 29(6):698-703. doi:10.1177/0269881115574493
44. Barratt MJ, Cakic V, Lenton S. Patterns of synthetic cannabinoid use in Australia. Drug Alcohol Rev (2013) 32(2):141-6. doi:10.1111/j.1465-3362.2012. 00519.x
45. Champion KE, Teesson M, Newton NC. Patterns and correlates of new psychoactive substance use in a sample of Australian high school students. Drug Alcohol Rev (2016) 35(3):338-44. doi:10.1111/dar.12312
46. Wood KE. Exposure to bath salts and synthetic tetrahydrocannabinol from 2009 to 2012 in the United States. J Pediatr (2013) 163(1):213-6. doi:10.1016/j.jpeds.2012.12.056
47. Baumann MH, Partilla JS, Lehner KR. Psychoactive "bath salts": not so soothing. Eur J Pharmacol (2013) 698(1-3):1-5. doi:10.1016/j.ejphar.2012. 11.020
48. Kelly BC, Wells BE, Pawson M, LeClair A, Parsons JT, Golub SA. Novel psychoactive drug use among younger adults involved in US nightlife scenes. Drug Alcohol Rev (2013) 32(6):588-93. doi:10.1111/dar.12058
49. Marusich JA, Grant KR, Blough BE, Wiley JL. Effects of synthetic cathinones contained in "bath salts" on motor behavior and a functional observational battery in mice. Neurotoxicology (2012) 33(5):1305-13. doi:10.1016/j. neuro.2012.08.003
50. Marusich JA, Antonazzo KR, Wiley JL, Blough BE, Partilla JS, Baumann MH. Pharmacology of novel synthetic stimulants structurally related to the "bathsalts" constituent 3,4-methylenedioxypyrovalerone (MDPV). Neuropharmacology (2014) 87:206-13. doi:10.1016/j.neuropharm. 2014.02.016
51. Saha K, Partilla JS, Lehner KR, Seddik A, Stockner T, Holy M, et al. 'Second- generation' mephedrone analogs, 4-MEC and 4-MePPP, differentially affect monoamine transporter function. Neuropsychopharmacology (2015) 40(6):1321-31. doi:10.1038/npp.2014.325
52. Watterson LR, Burrows BT, Hernandez RD, Moore KN, Grabenauer M, Marusich JA, et al. Effects of a-pyrrolidinopentiophenone and 4-methyl-N-ethylcathinone, two synthetic cathinones commonly found in second-generation "bath salts," on intracranial self-stimulation thresholds in rats. Int J Neuropsychopharmacol (2014) 18(1):yu014. doi:10.1093/ijnp/ pyu014
53. Bonano JS, Glennon RA, De Felice LJ, Banks ML, Negus SS. Abuse-related and abuse-limiting effects of methcathinone and the synthetic "bath salts" cathinone analogs methylenedioxypyrovalerone (MDPV), methylone, and mephedrone on intracranial self-stimulation in rats. Psychopharmacology (2014) 231(1):199-207. doi:10.1007/s00213-013-3223-5
54. Gregg RA, Baumann MH, Partilla JS, Bonano JS, Vouga A, Tallarida CS, et al. Stereochemistry of mephedrone neuropharmacology: enantiomer-specific behavioural and neurochemical effects in rats. Br J Pharmacol (2015) 172(3):883-94. doi:10.1111/bph.12951
55. Watterson LR, Hood L, Sewalia K, Tomek SE, Yahn S, Johnson CT, et al. The reinforcing and rewarding effects of methylone, a synthetic cathinone commonly found in "bath salts". J Addict Res Ther (2012) (Suppl 9):002. doi:10.4172/2155-6105.S9-002
56. Watterson LR, Kufahl PR, Nemirovsky NE, Sewalia K, Grabenauer M, Thomas BF, et al. Potent rewarding and reinforcing effects of the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV). Addict Biol (2014) 19(2):165-74. doi:10.1111/j.1369-1600.2012.00474.x
57. Botanas CJ, Yoon SS, de la Peña JB, Dela Peña IJ, Kim M, Woo T, et al. The abuse potential of a-piperidinopropiophenone (PIPP) and a-piperidinopentiothiophenone (PIVT), two new synthetic cathinones with piperidine ring substituent. Biomol Ther (Seoul) (2017) 25(2):122-9. doi:10.4062/ biomolther.2016.241
58. Botanas CJ, Yoon SS, de la Peña JB, Dela Peña IJ, Kim M, Woo T, et al. The abuse potential of two novel synthetic cathinones with modification on the alpha-carbon position, 2-cyclohexyl-2-(methylamino)-1-phenylethanone (MACHP) and 2-(methylamino)-1-phenyloctan-1-one (MAOP), and their effects on dopaminergic activity. Pharmacol Biochem Behav (2017) 153:160-7. doi:10.1016/j.pbb.2016.12.017
59. Botanas CJ, Yoon SS, de la Peña JB, Dela Peña IJ, Kim M, Woo T, et al. A novel synthetic cathinone, 2-(methylamino)-1-(naphthalen-2-yl) propan-1-one (BMAPN), produced rewarding effects and altered striatal dopamine-related gene expression in mice. Behav Brain Res (2017) 317:494-501. doi:10.1016/j. bbr.2016.10.016
60. Cheong JH, Choi MJ, Jang CG, Lee YS, Lee S, Kim HJ, et al. Behavioral evidence for the abuse potential of the novel synthetic cathinone alpha-pyrrolidinopentiothiophenone (PVT) in rodents. Psychopharmacology (2017) 234(5):857-67. doi:10.1007/s00213-017-4526-8
61. Oh JH, Hwang JY, Hong SI, Ma SX, Seo JY, Lee SY, et al. The new designer drug buphedrone produces rewarding properties via dopamine D1 receptor activation. Addict Biol (2016). doi:10.1111/adb.12472
62. Huskinson SL, Naylor JE, Townsend EA, Rowlett JK, Blough BE, Freeman KB. Self-administration and behavioral economics of second- generation synthetic cathinones in male rats. Psychopharmacology (2017) 234(4):589-98. doi:10.1007/s00213-016-4492-6
63. Karlsson L, Andersson M, Kronstrand R, Kugelberg FC. Mephedrone, methylone and 3,4-methylenedioxypyrovalerone (MDPV) induce conditioned place preference in mice. Basic Clin Pharmacol Toxicol (2014) 115(5):411-6. doi:10.1111/bcpt.12253
64. Gatch MB, Rutledge MA, Forster MJ. Discriminative and locomotor effects of five synthetic cathinones in rats and mice. Psychopharmacology (2015) 232(7):1197-205. doi:10.1007/s00213-014-3755-3
65. Gregg RA, Hicks C, Nayak SU, Tallarida CS, Nucero P, Smith GR, et al. Synthetic cathinone MDPV downregulates glutamate transporter subtype I (GLT-1) and produces rewarding and locomotor-activating effects that are reduced by a GLT-1 activator. Neuropharmacology (2016) 108:111-9. doi:10.1016/j.neuropharm.2016.04.014
66. Xu P, Qiu Y, Zhang Y, Bai Y, Xu P, Liu Y, et al. The effects of 4-methylethcathinone on conditioned place preference, locomotor sensitization, and anxiety-like behavior: a comparison with methamphetamine. Int J Neuropsychopharmacol (2016) 19(4):yv120. doi:10.1093/ijnp/ pyv120
67. King HE, Wakeford A, Taylor W, Wetzell B, Rice KC, Riley AL. Sex differences in 3,4-methylenedioxypyrovalerone (MDPV)-induced taste avoidance and place preferences. Pharmacol Biochem Behav (2015) 137:16-22. doi:10.1016/j.pbb.2015.07.013
68. Naylor JE, Freeman KB, Blough BE, Woolverton WL, Huskinson SL. Discriminative-stimulus effects of second generation synthetic cathinones in methamphetamine-trained rats. Drug Alcohol Depend (2015) 149:280-4. doi:10.1016/j.drugalcdep.2015.02.002
69. Gatch MB, Dolan SB, Forster MJ. Comparative behavioral pharmacology of three pyrrolidine-containing synthetic cathinone derivatives. J Pharmacol Exp Ther (2015) 354(2):103-10. doi:10.1124/jpet.115.223586
70. Penders TM, Gestring RE, Vilensky DA. Excited delirium following use of synthetic cathinones (bath salts). Gen Hosp Psychiatry (2012) 34(6):647-50. doi:10.1016/j.genhosppsych.2012.06.005
71. John ME, Thomas-Rozea C, Hahn D. Bath salts abuse leading to new onset psychosis and potential for violence. Clin Schizophr Relat Psychoses (2014) 20:1-14. doi:10.3371/CSRP.JORO.061314
72. Marinetti LJ, Antonides HM. Analysis of synthetic cathinones commonly found in bath salts in human performance and postmortem toxicology: method development, drug distribution and interpretation of results. J Anal Toxicol (2013) 37(3):135-46. doi:10.1093/jat/bks136
73. Barrios L, Grison-Hernando H, Boels D, Bouquie R, Monteil-Ganiere C, Clement R. Death following ingestion of methylone. Int J Legal Med (2016) 130(2):381-5. doi:10.1007/s00414-015-1212-4
74. Forrester MB. Synthetic cathinone exposures reported to Texas poison centers. Am J Drug Alcohol Abuse (2012) 38(6):609-15. doi:10.3109/00952 990.2012.677890
75. Paillet-Loilier M, Cesbron A, Le Boisselier R, Bourgine J, Debruyne D. Emerging drugs of abuse: current perspectives on substituted cathinones. Subst Abuse Rehabil (2014) 5:37-52. doi:10.2147/SAR.S37257
76. Sivagnanam K, Chaudari D, Lopez P, Sutherland ME, Ramu VK. "Bath salts" induced severe reversible cardiomyopathy. Am J Case Rep (2013) 14:288-91. doi:10.12659/AJCR.889381
77. Tekulve K, Alexander A, Tormoehlen L. Seizures associated with synthetic cathinone exposures in the pediatric population. Pediatr Neurol (2014) 51(1):67-70. doi:10.1016/j.pediatrneurol.2014.03.003
78. Pichini S, Rotolo MC, García J, Girona N, Leal L, García-Algar O, et al. Neonatal withdrawal syndrome after chronic maternal consumption of 4-methylethcathinone. Forensic Sci Int (2014) 245:e33-5. doi:10.1016/j. forsciint.2014.10.027
79. Mayer FP, Wimmer L, Dillon-Carter O, Partilla JS, Burchardt NV, Mihovilovic MD, et al. Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters. Br J Pharmacol (2016) 173(17):2657-68. doi:10.1111/bph.13547
80. Baumann MH, Bukhari MO, Lehner KR, Anizan S, Rice KC, Concheiro M, et al. Neuropharmacology of 3,4-methylenedioxypyrovalerone (MDPV), its metabolites, and related analogs. Curr Top Behav Neurosci (2017) 32:93-117. doi:10.1007/7854_2016_53
81. Anizan S, Concheiro M, Lehner KR, Bukhari MO, Suzuki M, Rice KC, et al. Linear pharmacokinetics of 3,4-methylenedioxypyrovalerone (MDPV) and its metabolites in the rat: relationship to pharmacodynamic effects. Addict Biol (2016) 21(2):339-47. doi:10.1111/adb.12201 82.
82. Spaderna M, Addy PH, D'Souza DC. Spicing things up: synthetic cannabinoids. Psychopharmacology (2013) 228(4):525-40. doi:10.1007/ s00213-013-3188-4
83. Fantegrossi WE, Moran JH, Radominska-Pandya A, Prather PL. Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to δ (9)-THC: mechanism underlying greater toxicity? Life Sci (2014) 97(1):45-54. doi:10.1016/j.lfs.2013.09.017
84. Atwood BK, Huffman J, Straiker A, Mackie K. JWH018, a common constituent of 'spice' herbal blends, is a potent and efficacious cannabinoid CB receptor agonist. Br J Pharmacol (2010) 160:585-93. doi:10.1111/j.1476-5381.2009.00582.x
85. Atwood BK, Lee D, Straiker A, Widlanski TS, Mackie K. CP47,497-C8 and JWH073, commonly found in 'spice' herbal blends, are potent and efficacious CB(1) cannabinoid receptor agonists. Eur J Pharmacol (2011) 659:139-45. doi: 10.1016/j.ejphar.2011.01.066
86. Huffman JW, Padgett LW. Recent developments in the medicinal chemistry of cannabimimetic indoles, pyrroles and indenes. Curr Med Chem (2005) 12:1395-411. doi:10.2174/0929867054020864
87. Huffman JW, Zengin G, Wu MJ, Lu J, Hynd G, Bushell K, et al. Structure- activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists. Bioorg Med Chem (2005) 13:89-112. doi:10.1016/j.bmc.2004.09.050
88. Lindigkeit R, Boehme A, Eiserloh I, Luebbecke M, Wiggermann M, Ernst L, et al. Spice: a never ending story? Forensic Sci Int (2009) 191:58-63. doi:10.1016/j.forsciint.2009.06.008
89. Marriott KS, Huffman JW. Recent advances in the development of selective ligands for the cannabinoid CB(2) receptor. Curr Top Med Chem (2008) 8:187-204. doi:10.2174/156802608783498014
90. Brown K. New Zealand bans synthetic cannabinoids. BMJ (2011) 343:d5395. doi:10.1136/bmj.d5395
91. Dresen S, Ferreiros N, Putz M, Westphal F, Zimmermann R, Auwarter V. Monitoring of herbal mixtures potentially containing synthetic cannabinoids as psychoactive compounds. J Mass Spectrom (2010) 45:1186-94. doi:10.1002/jms.1811
92. Zuba D, Byrska B, Maciow M. Comparison of "herbal highs" composition. Anal Bioanal Chem (2011) 400:119-26. doi:10.1007/s00216-011-4743-7
93. Wiebelhaus JM, Poklis JL, Poklis A, Vann RE, Lichtman AH, Wise LE. Inhalation exposure to smoke from synthetic "marijuana" produces potent cannabimimetic effects in mice. Drug Alcohol Depend (2012) 126(3):316-23. doi:10.1016/j.drugalcdep.2012.05.034
94. Marshell R, Kearney-Ramos T, Brents LK, Hyatt WS, Tai S, Prather PL, et al. In vivo effects of synthetic cannabinoids JWH-018 and JWH-073 and phytocannabinoid δ9-THC in mice: inhalation versus intraperitoneal injection. Pharmacol Biochem Behav (2014) 124:40-7. doi:10.1016/j. pbb.2014.05.010
95. Gatch MB, Forster MJ. δ9-Tetrahydrocannabinol-like discriminative stimulus effects of compounds commonly found in K2/Spice. Behav Pharmacol (2014) 25(8):750-7. doi:10.1097/FBP.0000000000000093
96. Gatch MB, Forster MJ. δ9-Tetrahydrocannabinol-like effects of novel synthetic cannabinoids found on the gray market. Behav Pharmacol (2015) 26(5):460-8. doi:10.1097/FBP.0000000000000150
97. Wiley JL, Marusich JA, Lefever TW, Antonazzo KR, Wallgren MT, Cortes RA, et al. AB-CHMINACA, AB-PINACA, and FUBIMINA: affinity and potency of novel synthetic cannabinoids in producing δ9-tetrahydrocannabinol-like effects in mice. J Pharmacol Exp Ther (2015) 354(3):328-39. doi:10.1124/ jpet.115.225326
98. Vigolo A, Ossato A, Trapella C, Vincenzi F, Rimondo C, Seri C, et al. Novel halogenated derivates of JWH-018: behavioral and binding studies in mice. Neuropharmacology (2015) 95:68-82. doi:10.1016/j.neuropharm. 2015.02.008
99. Ossato A, Vigolo A, Trapella C, Seri C, Rimondo C, Serpelloni G, et al. JWH-018 impairs sensorimotor functions in mice. Neuroscience (2015) 300:174-88. doi:10.1016/j.neuroscience.2015.05.021
100. Cha HJ, Lee KW, Song MJ, Hyeon YJ, Hwang JY, Jang CG, et al. Dependence potential of the synthetic cannabinoids JWH-073, JWH-081, and JWH-210: in vivo and in vitro approaches. Biomol Ther (Seoul) (2014) 22(4):363-9. doi:10.4062/biomolther.2014.039
101. Tampus R, Yoon SS, de la Peña JB, Botanas CJ, Kim HJ, Seo JW, et al. Assessment of the abuse liability of synthetic cannabinoid agonists JWH- 030, JWH-175, and JWH-176. Biomol Ther (Seoul) (2015) 23(6):590-6. doi:10.4062/biomolther.2015.120
102. Gatch MB, Forster MJ. δ(9)-Tetrahydrocannabinol-like effects of novel synthetic cannabinoids in mice and rats. Psychopharmacology (2016) 233(10):1901-10. doi:10.1007/s00213-016-4237-6
103. Wiley JL, Lefever TW, Marusich JA, Craft RM. Comparison of the discriminative stimulus and response rate effects of δ9-tetrahydrocannabinol and synthetic cannabinoids in female and male rats. Drug Alcohol Depend (2017) 172:51-9. doi:10.1016/j.drugalcdep.2016
104. Rodriguez JS, McMahon LR. JWH-018 in rhesus monkeys: differential antagonism of discriminative stimulus, rate-decreasing, and hypothermic effects. Eur J Pharmacol (2014) 740:151-9. doi:10.1016/j.ejphar.2014. 06.023
105. Hruba L, McMahon LR. Apparent affinity estimates and reversal of the effects of synthetic cannabinoids AM-2201, CP-47,497, JWH-122, and JWH-250 by rimonabant in rhesus monkeys. J Pharmacol Exp Ther (2017) 362(2):278-86. doi:10.1124/jpet.117.240572
106. Wilkinson ST, Radhakrishnan R, D'Souza DC. Impact of cannabis use on the development of psychotic disorders. Curr Addict Rep (2014) 1(2):115-28. doi:10.1007/s40429-014-0018-7
107. Radhakrishnan R, Wilkinson ST, D'Souza DC. Gone to pot-a review of the association between cannabis and psychosis. Front Psychiatry (2014) 5:54. doi:10.3389/fpsyt.2014.00054
108. van Amsterdam J, Brunt T, van den Brink W. The adverse health effects of synthetic cannabinoids with emphasis on psychosis-like effects. J Psychopharmacol (2015) 29(3):254-63. doi:10.1177/0269881114565142
109. Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimarães FS. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos Trans R Soc Lond B Biol Sci (2012) 367:3364-78. doi:10.1098/rstb.2011.0389
110. Fattore L. Synthetic cannabinoids-further evidence supporting the relationship between cannabinoids and psychosis. Biol Psych (2016) 79:539-48. doi:10.1016/j.biopsych.2016.02.001
111. Celofiga A, Koprivsek J, Klavz J. Use of synthetic cannabinoids in patients with psychotic disorders: case series. J Dual Diagn (2014) 10(3):168-73. doi:10.1080/15504263.2014.929364
112. Meijer KA, Russo RR, Adhvaryu DV. Smoking synthetic marijuana leads to self-mutilation requiring bilateral amputations. Orthopedics (2014) 37(4):e391-4. doi:10.3928/01477447-20140401-62
113. Ustundag MF, Ozhan Ibis E, Yucel A, Ozcan H. Synthetic cannabis- induced mania. Case Rep Psychiatry (2015) 2015:310930. doi:10.1155/2015/ 310930
114. Thomas S, Bliss S, Malik M. Suicidal ideation and self-harm following K2 use. J Okla State Med Assoc (2012) 105(11):430-3.
115. Lubman DI, Cheetham A, Yücel M. Cannabis and adolescent brain development. Pharmacol Ther (2015) 148:1-16. doi:10.1016/j.pharmthera. 2014.11.009
116. Nurmedov S, Metin B, Ekmen S, Noyan O, Yilmaz O, Darcin A, et al. Thalamic and cerebellar gray matter volume reduction in synthetic cannabinoids users. Eur Addict Res (2015) 21(6):315-20. doi:10.1159/000430437
117. Rominger A, Cumming P, Xiong G, Koller G, Förster S, Zwergal A, et al. Effects of acute detoxification of the herbal blend 'spice gold' on dopamine D2/3 receptor availability: a [18F]fallypride PET study. Eur Neuropsychopharmacol (2013) 23(11):1606-10. doi:10.1016/j.euroneuro.2013.01.009
118. Yeakel JK, Logan BK. Blood synthetic cannabinoid concentrations in cases of suspected impaired driving. J Anal Toxicol (2013) 37(8):547-51. doi:10.1093/ jat/bkt065
119. Jaenicke NJ, Pogoda W, Paulke A, Wunder C, Toennes SW. Retrospective analysis of synthetic cannabinoids in serum samples-epidemiology and consumption patterns. Forensic Sci Int (2014) 242:81-7. doi:10.1016/j. forsciint.2014.06.010
120. Musshoff F, Madea B, Kernbach-Wighton G, Bicker W, Kneisel S, Hutter M, et al. Driving under the influence of synthetic cannabinoids ("spice"): a case series. Int J Legal Med (2014) 128(1):59-64. doi:10.1007/ s00414-013-0864-1
121. Adamowicz P, Lechowicz W. The influence of synthetic cannabinoid UR-144 on human psychomotor performance-a case report demonstrating road traffic risks. Traffic Inj Prev (2015) 20:1-6. doi:10.1080/15389588.2015.101 8990
122. Tuv SS, Krabseth H, Karinen R, Olsen KM, Oøiestad EL, Vindenes V. Prevalence of synthetic cannabinoids in blood samples from Norwegian drivers suspected of impaired driving during a seven weeks period. Accid Anal Prev (2014) 62:26-31. doi:10.1016/j.aap.2013.09.009
123. Karinen R, Tuv SS, Oøiestad EL, Vindenes V. Concentrations of APINACA, 5F-APINACA, UR-144 and its degradant product in blood samples from six impaired drivers compared to previous reported concentrations of other synthetic cannabinoids. Forensic Sci Int (2015) 246:98-103. doi:10.1016/j. forsciint.2014.11.012
124. Trecki J, Gerona RR, Schwartz MD. Synthetic cannabinoid-related illnesses and deaths. N Engl J Med (2015) 373(2):103-7. doi:10.1056/ NEJMp1505328
125. Bonnet U, Mahler H. Synthetic cannabinoids: spread, addiction biology & current perspective of personal health hazard. Fortschr Neurol Psychiatr (2015) 83(4):221-31. doi:10.1055/s-0034-1399307
126. Shanks KG, Winston D, Heidingsfelder J, Behonick G. Case reports of synthetic cannabinoid XLR-11 associated fatalities. Forensic Sci Int (2015) 252:e6-9. doi:10.1016/j.forsciint.2015.04.021
127. Besli GE, Ikiz MA, Yildirim S, Saltik S. Synthetic cannabinoid abuse in adolescents: a case series. Emerg Med (2015) 49(5):644-50. doi:10.1016/j. jemermed.2015.06.053
128. Bernson-Leung ME, Leung LY, Kumar S. Synthetic cannabis and acute ischemic stroke. J Stroke Cerebrovasc Dis (2014) 23(5):1239-41. doi:10.1016/j. jstrokecerebrovasdis.2013.07.030
129. Louh IK, Freeman WD. A 'spicy' encephalopathy: synthetic cannabinoids as cause of encephalopathy and seizure. Crit Care (2014) 18(5):553. doi:10.1186/ s13054-014-0553-6
130. Gugelmann H, Gerona R, Li C, Tsutaoka B, Olson KR, Lung D. 'Crazy monkey' poisons man and dog: human and canine seizures due to PB-22, a novel synthetic cannabinoid. Clin Toxicol (2014) 52(6):635-8. doi:10.3109/ 15563650.2014.925562
131. Takematsu M, Hoffman RS, Nelson LS, Schechter JM, Moran JH, Wiener SW. A case of acute cerebral ischemia following inhalation of a synthetic cannabinoid. Clin Toxicol (2014) 52(9):973-5. doi:10.3109/ 15563650.2014.958614
132. Atik SU, Dedeoglu R, Varol F, çam H, Eroglu AG, Saltik L. Cardiovascular side effects related with use of synthetic cannabinoids "bonsai" two case reports. Turk Pediatri Ars (2015) 50(1):61-4. doi:10.5152/tpa.2015.2609
133. Heath TS, Burroughs Z, Thompson AJ, Tecklenburg FW. Acute intoxication caused by a synthetic cannabinoid in two adolescents. J Pediatr Pharmacol Ther (2012) 17(2):177-81. doi:10.5863/1551-6776-17.2.177
134. McKeever RG, Vearrier D, Jacobs D, LaSala G, Okaneku J, Greenberg MI. K2-not the spice of life; synthetic cannabinoids and ST elevation myocardial infarction: a case report. J Med Toxicol (2015) 11(1):129-31. doi:10.1007/ s13181-014-0424-1
135. Ibrahim S, Al-Saffar F, Wannenburg T. A unique case of cardiac arrest following K2 abuse. Case Rep Cardiol (2014) 2014:120607. doi:10.1155/2014/ 120607
136. Davis C, Boddington D. Teenage cardiac arrest following abuse of synthetic cannabis. Heart Lung Circ (2015) 24(10):e162-3. doi:10.1016/j. hlc.2015.04.176
137. Gudsoorkar VS, Perez JA Jr. A new differential diagnosis: synthetic cannabinoids-associated acute renal failure. Methodist Debakey Cardiovasc J (2015) 11(3):189-91. doi:10.14797/mdcj-11-3-189
138. Jinwala FN, Gupta M. Synthetic cannabis and respiratory depression. J Child Adolesc Psychopharmacol (2012) 22(6):459-62. doi:10.1089/cap.2011.0122
139. Alhadi S, Tiwari A, Vohra R, Gerona R, Acharya J, Bilello K. High times, low sats: diffuse pulmonary infiltrates associated with chronic synthetic cannabinoid use. J Med Toxicol (2013) 9(2):199-206. doi:10.1007/s13181-013-0288-9
140. Berkowitz EA, Henry TS, Veeraraghavan S, Staton GW Jr, Gal AA. Pulmonary effects of synthetic marijuana: chest radiography and CT findings. AJR Am J Roentgenol (2015) 204(4):750-7. doi:10.2214/AJR.14.13138
141. Hopkins CY, Gilchrist BL. A case of cannabinoid hyperemesis syndrome caused by synthetic cannabinoids. J Emerg Med (2013) 45(4):544-6. doi:10.1016/j.jemermed.2012.11.034
142. Ukaigwe A, Karmacharya P, Donato A. A gut gone to pot: a case of cannabinoid hyperemesis syndrome due to K2, a synthetic cannabinoid. Case Rep Emerg Med (2014) 2014:167098. doi:10.1155/2014/167098
143. Nacca N, Vatti D, Sullivan R, Sud P, Su M, Marraffa J. The synthetic cannabinoid withdrawal syndrome. J Addict Med (2013) 7(4):296-8. doi:10.1097/ ADM.0b013e31828e1881
144. Macfarlane V, Christie G. Synthetic cannabinoid withdrawal: a new demand on detoxification services. Drug Alcohol Rev (2015) 34(2):147-53. doi:10.1111/dar.12225
145. Sheridan J, Butler R. They're legal so they're safe, right? What did the legal status of BZP party pills mean to young people in New Zealand. Int J Drug Policy (2010) 21:77-81. doi:10.1016/j.drugpo.2009.02.002
146. Hughes B, Griffith P. Regulatory approaches to new psychoactive substances (NPS) in the European Union. Addiction (2014) 108:1591-3. doi:10.1111/ add.12610
147. Patton AL, Seely KA, Chimalakonda KC, Tran JP, Trass M, Miranda A, et al. Targeted metabolomic approach for assessing human synthetic cannabinoid exposure and pharmacology. Anal Chem (2013) 85(19):9390-9. doi:10.1021/ ac4024704
148. Cannaert A, Storme J, Franz F, Auwärter V, Stove CP. Detection and activity profiling of synthetic cannabinoids and their metabolites with a newly developed bioassay. Anal Chem (2016) 88(23):11476-85. doi:10.1021/acs. analchem.6b02600
149. Drug Enforcement Administration, Department of Justice. Schedules of controlled substances: temporary placement of three synthetic cathinones in schedule I. Final order. Fed Regist (2011) 76:65371-5.
150. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Legal Approaches to Controlling New Psychoactive Substances. Luxembourg: Publications Office of the European Union (2015). ISBN: 978-92- 9168-776-3.
151. Rosca P, Bauer A, Khawaled R, Kahana E, Goldman K. The recent legal approach to new psychoactive substances regulation in Israel: does it work? J Civil Legal Sci (2015) 140:1-6. doi:10.4172/2169-0170.1000140
152. Wilkins C. A critical first assessment of the new pre-market approval regime for the new psycho-active substances (NPS) in New Zealand. Addiction (2014) 109:1580-6. doi:10.1111/add.12484