Psychostimulant effect of the synthetic cannabinoid JWH-018 and AKB48: Behavioral, neurochemical, and dopamine transporter scan imaging studies in mice

Frontiers in Psychiatry

Volumn 8, Issue AUG, 2017, Pages

  Ossato, Andrea ^a,b   Uccelli, Licia ^a   Bilel, Sabrine ^a   Canazza, Isabella ^a,b   Di Domenico, Giovanni ^a   Pasquali, Micol ^a   Pupillo, Gaia ^c   De Luca, Maria Antonietta ^d   Boschi, Alessandra ^a   Vincenzi, Fabrizio ^a   Rimondo, Claudia ^e   Beggiato, Sarah ^a   Ferraro, Luca ^a   Varani, Katia ^a   Borea, Pier Andrea ^a   Serpelloni, Giovanni ^f   De Giorgio, Fabio ^b   Marti, Matteo ^a,g  

^a UNIVERSITY OF FERRARA   (Italy)

^b CATHOLIC UNIVERSITY   (Italy)

^c LABORATORI NAZIONALI DI LEGNARO   (Italy)

^d UNIVERSITY OF CAGLIARI   (Italy)

^e UNIVERSITY OF VERONA   (Italy)

^f UNIVERSITY OF FLORIDA COLLEGE OF MEDICINE   (United States)

^g Section of Pharmacology   (Italy)

Author keywords

AKB48; Cocaine; Dopamine transporter; JWH 018; Microdialysis; Psychostimulants; SPECT CT imaging; Synthetic cannabinoids

Indexed keywords

EID: 85028341798     PISSN: None     EISSN: 16640640     Source Type: Journal    
DOI: 10.3389/fpsyt.2017.00130     Document Type: Article

References (89)

1. EMCDDA. EU Drug Markets Report: In-Depth Analysis. Luxembourg: EMCDDA-Europol Joint Publications, Publications Office of the European Union (2016). Available from: http://www.emcdda.europa.eu/publications/ joint-publications/eu-drug-markets-2016-in-depth-analysis
2. EMCDDA. European Monitoring Centre for Drugs and Drug Addiction, European Drug Report 2016: Trends and Developments. Luxembourg: Publications Office of the European Union (2016). Available from: http:// www.emcdda.europa.eu/system/files/publications/2637/TDAT16001ENN. pdf
3. White CM. The pharmacologic and clinical effects of illicit synthetic cannabinoids.v J Clin Pharmacol (2017) 57(3):297-304. doi:10.1002/jcph.827
4. European Monitoring Centre for Drugs and Drug Addiction. Thematic Paper-Understanding the 'Spice' Phenomenon. Lisbon, Portugal: European Monitoring Centre for Drugs and Drug Addiction (2009).
5. NFLIS. Annual Report. (2013). Available from: http://www.deadiversion. usdoj.gov/nflis/NFLIS2013AR.pdf
6. 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
7. Canazza I, Ossato A, Trapella C, Fantinati A, De Luca MA, Margiani G, et al. Effect of the novel synthetic cannabinoids AKB48 and 5F-AKB48 on "tetrad", sensorimotor, neurological and neurochemical responses in mice. In vitro and in vivo pharmacological studies. Psychopharmacology (2016) 233(21-22):3685-709. doi:10.1007/s00213-016-4402-y
8. Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology (2010) 35(1):217-38. doi:10.1038/npp.2009.110
9. 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
10. Ossato A, Canazza I, Trapella C, Vincenzi F, De Luca MA, Rimondo C, et al. Effect of JWH-250, JWH-073 and their interaction on "tetrad", sensorimotor, neurological and neurochemical responses in mice. Prog Neuropsychopharmacol Biol Psychiatry (2016) 67:31-50. doi:10.1016/j. pnpbp.2016.01.007
11. Di Chiara G, Bassareo V, Fenu S, De Luca MA, Spina L, Cadoni C, et al. Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology (2004) 47(Suppl 1):227-41. doi:10.1016/j. neuropharm.2004.06.032
12. 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
13. Brewer TL, Collins M. A review of clinical manifestations in adolescent and young adults after use of synthetic cannabinoids. J Spec Pediatr Nurs (2014) 19(2):119-26. doi:10.1111/jspn.12057
14. Tournebize J, Gibaja V, Kahn JP. Acute effects of synthetic cannabinoids: update 2015. Subst Abuse (2016):1-23. doi:10.1080/08897077.2016.1219438
15. Cooper ZD. Adverse effects of synthetic cannabinoids: management of acute toxicity and withdrawal. Curr Psychiatry Rep (2016) 18(5):52. doi:10.1007/ s11920-016-0694-1
16. 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
17. Barbieri M, Ossato A, Canazza I, Trapella C, Borelli AC, Beggiato S, et al. Synthetic cannabinoid JWH-018 and its halogenated derivatives JWH-018-Cl and JWH-018-Br impair novel object recognition in mice: behavioral, electrophysiological and neurochemical evidence. Neuropharmacology (2016) 109:254-69. doi:10.1016/j.neuropharm.2016.06.027
18. Zubrycki EM, Giordano M, Sanberg PR. The effects of cocaine on multivariate locomotor behavior and defecation. Behav Brain Res (1990) 36(1-2):155-9. doi:10.1016/0166-4328(90)90169-F
19. Broderick PA, Rahni DN, Zhou Y. Acute and subacute effects of risperidone and cocaine on accumbens dopamine and serotonin release using in vivo microvoltammetry on line with open-field behavior. Prog Neuropsychopharmacol Biol Psychiatry (2003) 27(6):1037-54. doi:10.1016/s0278-5846(03)00176-3
20. Jiang Q, Wang CM, Fibuch EE, Wang JQ, Chu XP. Differential regulation of locomotor activity to acute and chronic cocaine administration by acid-sensing ion channel 1a and 2 in adult mice. Neuroscience (2013) 246:170-8. doi:10.1016/j.neuroscience.2013.04.059
21. Simchon-Tenenbaum Y, Weizman A, Rehavi M. Alterations in brain neurotrophic and glial factors following early age chronic methylphenidate and cocaine administration. Behav Brain Res (2015) 282:125-32. doi:10.1016/j. bbr.2014.12.058
22. Zombeck JA, Swearingen SP, Rhodes JS. Acute locomotor responses to cocaine in adolescents vs. adults from four divergent inbred mouse strains. Genes Brain Behav (2010) 9(8):892-8. doi:10.1111/j.1601-183X.2010.00630.x
23. Sanberg PR, Henault MA, Hagenmeyer-Houser SH, Russell KH. The topography of amphetamine and scopolamine-induced hyperactivity: toward an activity print. Behav Neurosci (1987) 101(1):131-3. doi:10.1037/0735-7044. 101.1.131
24. Laviola G, Dell'Omo G, Chiarotti F, Bignami G. d-Amphetamine conditioned place preference in developing mice: relations with changes in activity and stereotypies. Behav Neurosci (1994) 108(3):514-24. doi:10.1037/0735-7044.108.3.514
25. Proietti Onori M, Ceci C, Laviola G, Macri S. A behavioural test battery to investigate tic-like symptoms, stereotypies, attentional capabilities, and spontaneous locomotion in different mouse strains. Behav Brain Res (2014) 267:95-105. doi:10.1016/j.bbr.2014.03.023
26. De Luca MA, Castelli MP, Loi B, Porcu A, Martorelli M, Miliano C, et al. Native CB1 receptor affinity, intrinsic activity and accumbens shell dopamine stimulant properties of third generation SPICE/K2 cannabinoids: BB-22, 5F-PB-22, 5F-AKB-48 and STS-135. Neuropharmacology (2016) 105:630-8. doi:10.1016/j.neuropharm.2015.11.017
27. Cheng MH, Block E, Hu F, Cobanoglu MC, Sorkin A, Bahar I. Insights into the modulation of dopamine transporter function by amphetamine, orphenadrine, and cocaine binding. Front Neurol (2015) 6:134. doi:10.3389/ fneur.2015.00134
28. Ferraro L, Beggiato S, Marcellino D, Frankowska M, Filip M, Agnati LF, et al. Nanomolar concentrations of cocaine enhance D2-like agonist-induced inhibition of the K+-evoked [3H]-dopamine efflux from rat striatal synaptosomes: a novel action of cocaine. J Neural Transm (Vienna) (2010) 117(5):593-7. doi:10.1007/s00702-010-0389-4
29. Binda F, Dipace C, Bowton E, Robertson SD, Lute BJ, Fog JU, et al. Syntaxin 1A interaction with the dopamine transporter promotes amphetamine-induced dopamine efflux. Mol Pharmacol (2008) 74(4):1101-8. doi:10.1124/ mol.108.048447
30. Del Guerra A, Bartoli A, Belcari N, Herbert D, Motta A, Vaiano A, et al. Performance evaluation of the fully engineered YAP-(S)PET scanner for small animal imaging. IEEE Trans Nucl Sci (2006) 53:1078-83. doi:10.1109/ TNS.2006.871900
31. Boschi A, Pasquali M, Uccelli L, Duatti A. Novel Tc-99m radiotracers for brain imaging. Braz Arch Biol Technol (2007) 50:37-44. doi:10.1590/ S1516-89132007000600005
32. Esposito E, Boschi A, Ravani L, Cortesi R, Drechsler M, Mariani P, et al. Biodistribution of nanostructured lipid carriers: a tomographic study. Eur J Pharm Biopharm (2015) 89:145-56. doi:10.1016/j.ejpb.2014.12.006
33. Smilkov K, Janevik E, Guerrini R, Pasquali M, Boschi A, Uccelli L, et al. Preparation and first biological evaluation of novel Re-188/Tc-99m peptide conjugates with substance-P. Appl Radiat Isot (2014) 92:25-31. doi:10.1016/j. apradiso.2014.06.003
34. NEMA. Performance Measurements of Small Animal Positron Emission Tomographs. Standard Publication NU 4-2008. Rosslyn, VA: National Electrical Manufacturers Association (2008).
35. Cittanti C, Uccelli L, Pasquali M, Boschi A, Flammia C, Bagatin E, et al. Whole-body biodistribution and radiation dosimetry of the new cardiac tracer 99mTc-N-DBODC. J Nucl Med (2008) 49(8):1299-304. doi:10.2967/ jnumed.108.053132
36. Di Domenico G, Cesca N, Zavattini G, Auricchi N, Gambaccini M. CT with a CMOS flat panel detector integrated on the YAP(S)PET scanner for in vivo small animal imaging. Nucl Instrum Methods Phys Res (2007) 571:110-3. doi:10.1016/j.nima.2006.10.042
37. Loening AM, Gambhir SS. AMIDE: a free software tool for multimodality medical image analysis. Mol Imaging (2003) 2(3):131-7. doi:10.1162/153535003322556877
38. MacKenzie-Graham A, Boline J, Toga AW. Brain atlases and neuroanatomic imaging. Methods Mol Biol (2007) 401:183-94. doi:10.1007/978-1- 59745-520-6_11
39. Ma Y, Hof PR, Grant SC, Blackband SJ, Bennett R, Slatest L, et al. A three-dimensional digital atlas database of the adult C57BL/6J mouse brain by magnetic resonance microscopy. Neuroscience (2005) 135(4):1203-15. doi:10.1016/j.neuroscience.2005.07.014
40. Paxinos G, Franklin KBJ. The Mouse Brain in Stereotaxic Coordinates. San Diego: Academic Press (2001).
41. 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
42. Canazza I, Ossato A, Vincenzi F, Gregori A, Di Rosa F, Nigro F, et al. Pharmaco-toxicological effects of the novel third-generation fluorinate synthetic cannabinoids, 5F-ADBINACA, AB-FUBINACA, and STS-135 in mice. In vitro and in vivo studies. Hum Psychopharmacol (2017) 32:e2601. doi:10.1002/hup.2601
43. Rodriguez de Fonseca F, Del Arco I, Martin-Calderon JL, Gorriti MA, Navarro M. Role of the endogenous cannabinoid system in the regulation of motor activity. Neurobiol Dis (1998) 5(6 Pt B):483-501.
44. Drews E, Schneider M, Koch M. Effects of the cannabinoid receptor agonist WIN 55,212-2 on operant behavior and locomotor activity in rats. Pharmacol Biochem Behav (2005) 80(1):145-50. doi:10.1016/j.pbb.2004.10.023
45. Breivogel CS, Childers SR. The functional neuroanatomy of brain cannabinoid receptors. Neurobiol Dis (1998) 5(6 Pt B):417-31. doi:10.1006/nbdi.1998.0229
46. Sanudo-Pena MC, Tsou K, Walker JM. Motor actions of cannabinoids in the basal ganglia output nuclei. Life Sci (1999) 65(6-7):703-13. doi:10.1016/ S0024-3205(99)00293-3
47. Sulcova E, Mechoulam R, Fride E. Biphasic effects of anandamide. Pharmacol Biochem Behav (1998) 59(2):347-52. doi:10.1016/S0091-3057(97)00422-X
48. Katsidoni V, Kastellakis A, Panagis G. Biphasic effects of δ9-tetrahydrocannabinol on brain stimulation reward and motor activity. Int J Neuropsychopharmacol (2013) 16:2273-84. doi:10.1017/S1461145713000709
49. Walsh RN, Cummins RA. The open-field test: a critical review. Psychol Bull (1976) 83(3):482-504. doi:10.1037/0033-2909.83.3.482
50. Simon P, Dupuis R, Costentin J. Thigmotaxis as an index of anxiety in mice. Influence of dopaminergic transmissions. Behav Brain Res (1994) 61(1):59-64. doi:10.1016/0166-4328(94)90008-6
51. Treit D, Fundytus M. Thigmotaxis as a test for anxiolytic activity in rats. Pharmacol Biochem Behav (1988) 31(4):959-62. doi:10.1016/0091-3057(88)90413-3
52. Haller J, Varga B, Ledent C, Freund TF. CB1 cannabinoid receptors mediate anxiolytic effects: convergent genetic and pharmacological evidence with CB1-specific agents. Behav Pharmacol (2004) 15(4):299-304. doi:10.1097/01. fbp.0000135704.56422.40
53. Macri S, Lanuzza L, Merola G, Ceci C, Gentili S, Valli A, et al. Behavioral responses to acute and sub-chronic administration of the synthetic cannabinoid JWH-018 in adult mice prenatally exposed to corticosterone. Neurotox Res (2013) 24(1):15-28. doi:10.1007/s12640-012-9371-2
54. Ennaceur A, Chazot PL. Preclinical animal anxiety research-flaws and prejudices. Pharmacol Res Perspect (2016) 4(2):e00223. doi:10.1002/prp2.223
55. Rey AA, Purrio M, Viveros MP, Lutz B. Biphasic effects of cannabinoids in anxiety responses: CB1 and GABA(B) receptors in the balance of GABAergic and glutamatergic neurotransmission. Neuropsychopharmacology (2012) 37(12):2624-34. doi:10.1038/npp.2012.123
56. Kinden R, Zhang X. Cannabinoids & stress: impact of HU-210 on behavioral tests of anxiety in acutely stressed mice. Behav Brain Res (2015) 284:225-30. doi:10.1016/j.bbr.2015.02.025
57. Flores A, Julia-Hernandez M, Maldonado R, Berrendero F. Involvement of the orexin/hypocretin system in the pharmacological effects induced by delta(9)-tetrahydrocannabinol. Br J Pharmacol (2016) 173(8):1381-92. doi:10.1111/bph.13440
58. Brecht M, Preilowski B, Merzenich MM. Functional architecture of the mystacial vibrissae. Behav Brain Res (1997) 84(1-2):81-97. doi:10.1016/ S0166-4328(97)83328-1
59. Mitchinson B, Prescott TJ. Whisker movements reveal spatial attention: a unified computational model of active sensing control in the rat. PLoS Comput Biol (2013) 9(9):e1003236. doi:10.1371/journal.pcbi.1003236
60. Yang XM, Gorman AL, Dunn AJ, Goeders NE. Anxiogenic effects of acute and chronic cocaine administration: neurochemical and behavioral studies. Pharmacol Biochem Behav (1992) 41(3):643-50. doi:10.1016/0091-3057(92)90386-T
61. Lin HQ, Burden PM, Christie MJ, Johnston GA. The anxiogenic-like and anxiolytic-like effects of MDMA on mice in the elevated plus-maze: a comparison with amphetamine. Pharmacol Biochem Behav (1999) 62(3):403-8. doi:10.1016/S0091-3057(98)00191-9
62. Cabib S, Castellano C, Cestari V, Filibeck U, Puglisi-Allegra S. D1 and D2 receptor antagonists differently affect cocaine-induced locomotor hyperactivity in the mouse. Psychopharmacology (1991) 105(3):335-9. doi:10.1007/ BF02244427
63. Gold LH, Geyer MA, Koob GF. Neurochemical mechanisms involved in behavioral effects of amphetamines and related designer drugs. NIDA Res Monogr (1989) 94:101-26.
64. Price DA, Owens WA, Gould GG, Frazer A, Roberts JL, Daws LC, et al. CB1-independent inhibition of dopamine transporter activity by cannabinoids in mouse dorsal striatum. J Neurochem (2007) 101(2):389-96. doi:10.1111/j.1471-4159.2006.04383.x
65. Pristupa ZB, Wilson JM, Hoffman BJ, Kish SJ, Niznik HB. Pharmacological heterogeneity of the cloned and native human dopamine transporter: disassociation of [3H]WIN 35,428 and [3H]GBR 12,935 binding. Mol Pharmacol (1994) 45(1):125-35.
66. Iversen L, Gibbons S, Treble R, Setola V, Huang XP, Roth BL. Neurochemical profiles of some novel psychoactive substances. Eur J Pharmacol (2013) 700(1-3):147-51. doi:10.1016/j.ejphar.2012.12.006
67. Howes J, Osgood P. The effect of delta9-tetrahydrocannabinol on the uptake and release of 14C-dopamine from crude striatal synaptosoma; preparations. Neuropharmacology (1974) 13(12):1109-14. doi:10.1016/0028-3908(74)90060-4
68. Banerjee SP, Snyder SH, Mechoulam R. Cannabinoids: influence on neurotransmitter uptake in rat brain synaptosomes. J Pharmacol Exp Ther (1975) 194(1):74-81.
69. Kofalvi A, Rodrigues RJ, Ledent C, Mackie K, Vizi ES, Cunha RA, et al. Involvement of cannabinoid receptors in the regulation of neurotransmitter release in the rodent striatum: a combined immunochemical and pharmacological analysis. J Neurosci (2005) 25(11):2874-84. doi:10.1523/ jneurosci.4232-04.2005
70. De Wit H, Wise RA. Blockade of cocaine reinforcement in rats with the dopamine receptor blocker pimozide, but not with the noradrenergic blockers phentolamine or phenoxybenzamine. Can J Psychol (1977) 31(4):195-203. doi:10.1037/h0081662
71. Church WH, Justice JB Jr, Byrd LD. Extracellular dopamine in rat striatum following uptake inhibition by cocaine, nomifensine and benztropine. Eur J Pharmacol (1987) 139(3):345-8. doi:10.1016/0014-2999(87)90592-9
72. Ritz MC, Cone EJ, Kuhar MJ. Cocaine inhibition of ligand binding at dopamine, norepinephrine and serotonin transporters: a structure-activity study. Life Sci (1990) 46(9):635-45. doi:10.1016/0024-3205(90)90132-B
73. Bradberry CW, Roth RH. Cocaine increases extracellular dopamine in rat nucleus accumbens and ventral tegmental area as shown by in vivo microdialysis. Neurosci Lett (1989) 103(1):97-102. doi:10.1016/0304-3940(89)90492-8
74. Hurd YL, Ungerstedt U. Ca2+ dependence of the amphetamine, nomifensine, and Lu 19-005 effect on in vivo dopamine transmission. Eur J Pharmacol (1989) 166(2):261-9. doi:10.1016/0014-2999(89)90067-8
75. Kalivas PW, Duffy P. Effect of acute and daily cocaine treatment on extracellular dopamine in the nucleus accumbens. Synapse (1990) 5(1):48-58. doi:10.1002/syn.890050104
76. Broderick PA. Cocaine: on-line analysis of an accumbens amine neural basis for psychomotor behavior. Pharmacol Biochem Behav (1991) 40(4):959-68. doi:10.1016/0091-3057(91)90112-F
77. Broderick PA. In vivo electrochemical studies of gradient effects of (SC) cocaine on dopamine and serotonin release in dorsal striatum of conscious rats. Pharmacol Biochem Behav (1993) 46(4):973-84. doi:10.1016/0091- 3057(93)90231-H
78. Broderick PA, Kornak EP Jr, Eng F, Wechsler R. Real time detection of acute (IP) cocaine-enhanced dopamine and serotonin release in ventrolateral nucleus accumbens of the behaving Norway rat. Pharmacol Biochem Behav (1993) 46(3):715-22. doi:10.1016/0091-3057(93)90567-D
79. Julian MD, Martin AB, Cuellar B, Rodriguez De Fonseca F, Navarro M, Moratalla R, et al. Neuroanatomical relationship between type 1 cannabinoid receptors and dopaminergic systems in the rat basal ganglia. Neuroscience (2003) 119(1):309-18. doi:10.1016/S0306-4522(03)00070-8
80. Covey DP, Mateo Y, Sulzer D, Cheer JF, Lovinger DM. Endocannabinoid modulation of dopamine neurotransmission. Neuropharmacology (2017). doi:10.1016/j.neuropharm.2017.04.033
81. Fitzgerald ML, Shobin E, Pickel VM. Cannabinoid modulation of the dopaminergic circuitry: implications for limbic and striatal output. Prog Neuropsychopharmacol Biol Psychiatry (2012) 38(1):21-9. doi:10.1016/j. pnpbp.2011.12.004
82. Melis M, Sagheddu C, De Felice M, Casti A, Madeddu C, Spiga S, et al. Enhanced endocannabinoid-mediated modulation of rostromedial tegmental nucleus drive onto dopamine neurons in Sardinian alcohol-preferring rats. J Neurosci (2014) 34(38):12716-24. doi:10.1523/jneurosci.1844-14.2014
83. Melis M, Frau R, Kalivas PW, Spencer S, Chioma V, Zamberletti E, et al. New vistas on cannabis use disorder. Neuropharmacology (2017). doi:10.1016/j. neuropharm.2017.03.033
84. Bowyer JF, Masserano JM, Weiner N. Inhibitory effects of amphetamine on potassium-stimulated release of [3H]dopamine from striatal slices and synaptosomes. J Pharmacol Exp Ther (1987) 240(1):177-86.
85. Szabo B, Muller T, Koch H. Effects of cannabinoids on dopamine release in the corpus striatum and the nucleus accumbens in vitro. J Neurochem (1999) 73(3):1084-9. doi:10.1046/j.1471-4159.1999.0731084.x
86. Hermanns-Clausen M, Kneisel S, Szabo B, Auwarter V. Acute toxicity due to the confirmed consumption of synthetic cannabinoids: clinical and laboratory findings. Addiction (2013) 108(3):534-44. doi:10.1111/j.1360-0443.2012.04078.x
87. Gurney SM, Scott KS, Kacinko SL, Presley BC, Logan BK. Pharmacology, toxicology, and adverse effects of synthetic cannabinoid drugs. Forensic Sci Rev (2014) 26:53-78.
88. Fattore L. Synthetic cannabinoids-further evidence supporting the relationship between cannabinoids and psychosis. Biol Psychiatry (2016) 79(7):539-48. doi:10.1016/j.biopsych.2016.02.001
89. Muller HH, Kornhuber J, Sperling W. The behavioral profile of spice and synthetic cannabinoids in humans. Brain Res Bull (2016) 126(Pt 1):3-7. doi:10.1016/j.brainresbull.2015.10.013