Cannabidiol as a potential treatment for psychosis

European Neuropsychopharmacology

Volumn 24, Issue 1, 2014, Pages 51-64

  Schubart, C D ^c   Sommer, I E C ^a   Fusar Poli, P ^b   de Witte, L ^a   Kahn, R S ^c   Boks, M P M ^a  

^a UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

^b KING'S COLLEGE LONDON   (United Kingdom)

^c TERGOOI HOSPITAL   (Netherlands)

Author keywords

Antipsychotics; Cannabidiol; Cannabis; Psychosis; Schizophrenia; Treatment

Indexed keywords

CANNABIDIOL; CANNABINOID; CANNABINOID RECEPTOR; ENDOCANNABINOID; NEUROLEPTIC AGENT;

DRUG TOLERABILITY; EXPERIMENTAL STUDY; HUMAN; IMMUNE RESPONSE; NEUROIMAGING; NONHUMAN; OUTCOME ASSESSMENT; PRIORITY JOURNAL; PSYCHOSIS; REVIEW;

ANTIPSYCHOTICS; CANNABIDIOL; CANNABIS; PSYCHOSIS; SCHIZOPHRENIA; TREATMENT;

ANIMALS; ANTIPSYCHOTIC AGENTS; CANNABIDIOL; DATABASES, BIBLIOGRAPHIC; HUMANS; PSYCHOTIC DISORDERS;

EID: 84892488292     PISSN: 0924977X     EISSN: 18737862     Source Type: Journal    
DOI: 10.1016/j.euroneuro.2013.11.002     Document Type: Review

References (173)

1. Arseneault L., Cannon M., Poulton R., Murray R., Caspi A., Moffitt T.E. Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. Br. Med. J. 2002, 325:1212-1213.
2. Arseneault L., Cannon M., Witton J., Murray R.M. Causal association between cannabis and psychosis: examination of the evidence. Br. J. Psychiatry 2004, 184:110-117.
3. Balenga N.A., Henstridge C.M., Kargl J., Waldhoer M. Pharmacology, signaling and physiological relevance of the G protein-coupled receptor 55. Adv. Pharmacol. 2011, 62:251-277.
4. Barichello T., Ceretta R.A., Generoso J.S., Moreira A.P., Simoes L.R., Comim C.M., Quevedo J., Vilela M.C., Zuardi A.W., Crippa J.A., Teixeira A.L. Cannabidiol reduces host immune response and prevents cognitive impairments in Wistar rats submitted to pneumococcal meningitis. Eur. J. Pharmacol. 2012, 697:158-164.
5. Batalla A., Crippa J.A., Busatto G.F., Guimaraes F.S., Zuardi A.W., Valverde O., Atakan Z., McGuire P.K., Bhattacharyya S., Martin-Santos R. Neuroimaging studies of acute effects of THC and CBD in humans and animals: a systematic review. Curr. Pharm. Des. 2013, ([epub ahead of print]).
6. Barkus E., Morrison P.D., Vuletic D., Dickson J.C., Ell P.J., Pilowsky L.S., Brenneisen R., Holt D.W., Powell J., Kapur S., Murray R.M. Does intravenous Delta9-tetrahydrocannabinol increase dopamine release? A SPET study. J. Psychopharmacol. 2011, 25:1462-1468.
7. Basu S., Dittel B.N. Unraveling the complexities of cannabinoid receptor 2 (CB2) immune regulation in health and disease. Immunol. Res. 2011, 51:26-38.
8. Bergamaschi M.M., Queiroz R.H., Zuardi A.W., Crippa J.A. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr. Drug Saf. 2011, 6:237-249.
9. Beumer W., Gibney S.M., Drexhage R.C., Pont-Lezica L., Doorduin J., Klein H.C., Steiner J., Connor T.J., Harkin A., Versnel M.A., Drexhage H.A. The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes. J. Leukoc. Biol. 2012, 92:959-975.
10. Bhattacharyya S., Atakan Z., Martin-Santos R., Crippa J.A., Kambeitz J., Prata D., Williams S., Brammer M., Collier D.A., McGuire P.K. Preliminary report of biological basis of sensitivity to the effects of cannabis on psychosis: AKT1 and DAT1 genotype modulates the effects of delta-9-tetrahydrocannabinol on midbrain and striatal function. Mol. Psychiatry 2012, 17:1152-1155.
11. Bhattacharyya S., Crippa J.A., Allen P., Martin-Santos R., Borgwardt S., Fusar-Poli P., Rubia K., Kambeitz J., O'Carroll C., Seal M.L., Giampietro V., Brammer M., Zuardi A.W., Atakan Z., McGuire P.K. Induction of psychosis by Delta9-tetrahydrocannabinol reflects modulation of prefrontal and striatal function during attentional salience processing. Arch. Gen. Psychiatry 2012, 69:27-36.
12. Bhattacharyya S., Fusar-Poli P., Borgwardt S., Martin-Santos R., Nosarti C., O'Carroll C., Allen P., Seal M.L., Fletcher P.C., Crippa J.A., Giampietro V., Mechelli A., Atakan Z., McGuire P. Modulation of mediotemporal and ventrostriatal function in humans by Delta9-tetrahydrocannabinol: a neural basis for the effects of Cannabis sativa on learning and psychosis. Arch. Gen. Psychiatry 2009, 66:442-451.
13. Bhattacharyya S., Morrison P.D., Fusar-Poli P., Martin-Santos R., Borgwardt S., Winton-Brown T., Nosarti C., O' Carroll C.M., Seal M., Allen P., Mehta M.A., Stone J.M., Tunstall N., Giampietro V., Kapur S., Murray R.M., Zuardi A.W., Crippa J.A., Atakan Z., McGuire P.K. Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology 2010, 35:764-774.
14. Bhattacharyya S., Atakan Z., Martin-Santos R., Crippa J.A., McGuire P.K. Neural mechanisms for the cannabinoid modulation of cognition and affect in man: a critical review of neuroimaging studies. Curr. Pharm. Des. 2012, 18:5045-5054.
15. Bisogno T., Hanus L., De P.L., Tchilibon S., Ponde D.E., Brandi I., Moriello A.S., Davis J.B., Mechoulam R., Di M.V. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br. J. Pharmacol. 2001, (134):845-852.
16. Borgwardt S.J., Allen P., Bhattacharyya S., Fusar-Poli P., Crippa J.A., Seal M.L., Fraccaro V., Atakan Z., Martin-Santos R., O'Carroll C., Rubia K., McGuire P.K. Neural basis of Delta-9-tetrahydrocannabinol and cannabidiol: effects during response inhibition. Biol. Psychiatry 2008, 64:966-973.
17. Bossong M.G., van Berckel B.N., Boellaard R., Zuurman L., Schuit R.C., Windhorst A.D., van Gerven J.M., Ramsey N.F., Lammertsma A.A., Kahn R.S. Delta9-tetrahydrocannabinol induces dopamine release in the human striatum. Neuropsychopharmacology 2008, 34:759-766.
18. Braff D.L., Geyer M.A., Light G.A., Sprock J., Perry W., Cadenhead K.S., Swerdlow N.R. Impact of prepulse characteristics on the detection of sensorimotor gating deficits in schizophrenia. Schizophr. Res. 2001, 49:171-178.
19. Brown A.J. Novel cannabinoid receptors. Br. J. Pharmacol. 2007, 152:567-575.
20. Cabral G.A., Griffin-Thomas L. Emerging role of the cannabinoid receptor CB2 in immune regulation: therapeutic prospects for neuroinflammation. Expert Rev. Mol. Med. 2009, 11:e3.
21. Caspi A., Moffitt T.E., Cannon M., McClay J., Murray R., Harrington H., Taylor A., Arseneault L., Williams B., Braithwaite A., Poulton R., Craig I.W. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene×environment interaction. Biol. Psychiatry 2005, 57:1117-1127.
22. Castillo P.E., Younts T.J., Chavez A.E., Hashimotodani Y. Endocannabinoid signaling and synaptic function. Neuron 2012, 76:70-81.
23. Chavarria-Siles I., Contreras-Rojas J., Hare E., Walss-Bass C., Quezada P., Dassori A., Contreras S., Medina R., Ramirez M., Salazar R., Raventos H., Escamilla M.A. Cannabinoid receptor 1 gene (CNR1) and susceptibility to a quantitative phenotype for hebephrenic schizophrenia. Am. J. Med. Genet .B: Neuropsychiatr. Genet. 2008, 147:279-284.
24. Chen J., Paredes W., Lowinson J.H., Gardner E.L. Delta 9-tetrahydrocannabinol enhances presynaptic dopamine efflux in medial prefrontal cortex. Eur. J. Pharmacol. 1990, 190:259-262.
25. Chen J.P., Paredes W., Li J., Smith D., Lowinson J., Gardner E.L. Delta 9-tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamine efflux in nucleus accumbens of conscious, freely-moving rats as measured by intracerebral microdialysis. Psychopharmacology (Berlin) 1990, 102:156-162.
26. Crippa J.A., Zuardi A.W., Martin-Santos R., Bhattacharyya S., Atakan Z., McGuire P., Fusar-Poli P. Cannabis and anxiety: a critical review of the evidence. Hum. Psychopharmacol. 2009, 24:515-523.
27. Cui M., Honore P., Zhong C., Gauvin D., Mikusa J., Hernandez G., Chandran P., Gomtsyan A., Brown B., Bayburt E.K., Marsh K., Bianchi B., McDonald H., Niforatos W., Neelands T.R., Moreland R.B., Decker M.W., Lee C.H., Sullivan J.P., Faltynek C.R. TRPV1 receptors in the CNS play a key role in broad-spectrum analgesia of TRPV1 antagonists. J. Neurosci. 2006, 26:9385-9393.
28. D'Souza D.C., bi-Saab W.M., Madonick S., Forselius-Bielen K., Doersch A., Braley G., Gueorguieva R., Cooper T.B., Krystal J.H. Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction. Biol. Psychiatry 2005, 57:594-608.
29. D'Souza D.C., Braley G., Blaise R., Vendetti M., Oliver S., Pittman B., Ranganathan M., Bhakta S., Zimolo Z., Cooper T., Perry E. Effects of haloperidol on the behavioral, subjective, cognitive, motor, and neuroendocrine effects of Delta-9-tetrahydrocannabinol in humans. Psychopharmacology (Berlin) 2008, 198:587-603.
30. Dalterio S., Steger R., Mayfield D., Bartke A. Early cannabinoid exposure influences neuroendocrine and reproductive functions in mice: II. Postnatal effects. Pharmacol. Biochem. Behav. 1984, 20:115-123.
31. Dalton V.S., Long L.E., Weickert C.S., Zavitsanou K. Paranoid schizophrenia is characterized by increased CB1 receptor binding in the dorsolateral prefrontal cortex. Neuropsychopharmacology 2011, 36:1620-1630.
32. Dalton W.S., Martz R., Lemberger L., Rodda B.E., Forney R.B. Influence of cannabidiol on delta-9-tetrahydrocannabinol effects. Clin. Pharmacol. Ther. 1976, 19:300-309.
33. Day H.E., Kryskow E.M., Nyhuis T.J., Herlihy L., Campeau S. Conditioned fear inhibits c-fos mRNA expression in the central extended amygdala. Brain Res. 2008, 1229:137-146.
34. De Filippis D., Esposito G., Cirillo C., Cipriano M., De Winter B.Y., Scuderi C., Sarnelli G., Cuomo R., Steardo L., De Man J.G., Iuvone T. Cannabidiol reduces intestinal inflammation through the control of neuroimmune axis. PloS One 2011, 6:e28159.
35. De Marchi N., De P.L., Orlando P., Daniele F., Fezza F., Di M.V. Endocannabinoid signalling in the blood of patients with schizophrenia. Lipids Health Dis. 2003, (2):5.
36. Dean B., Sundram S., Bradbury R., Scarr E., Copolov D. Studies on [3H]CP-55940 binding in the human central nervous system: regional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use. Neuroscience 2001, 103:9-15.
37. Demirakca T., Sartorius A., Ende G., Meyer N., Welzel H., Skopp G., Mann K., Hermann D. Diminished gray matter in the hippocampus of cannabis users: possible protective effects of cannabidiol. Drug Alcohol Depend. 2011, 114:242-245.
38. Devane W.A., Hanus L., Breuer A., Pertwee R.G., Stevenson L.A., Griffin G., Gibson D., Mandelbaum A., Etinger A., Mechoulam R. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992, 258:1946-1949.
39. Di Forti M., Iyegbe C., Sallis H., Kolliakou A., Falcone M.A., Paparelli A., Sirianni M., La C.C., Stilo S.A., Marques T.R., Handley R., Mondelli V., Dazzan P., Pariante C., David A.S., Morgan C., Powell J., Murray R.M. Confirmation that the AKT1 (rs2494732) genotype influences the risk of psychosis in cannabis users. Biol. Psychiatry 2012, 72:811-816.
40. Di Forti M., Morgan C., Dazzan P., Pariante C., Mondelli V., Marques T.R., Handley R., Luzi S., Russo M., Paparelli A., Butt A., Stilo S.A., Wiffen B., Powell J., Murray R.M. High-potency cannabis and the risk of psychosis. Br. J. Psychiatry 2009, 195:488-491.
41. Di Marzo V., Goparaju S.K., Wang L., Liu J., Batkai S., Jarai Z., Fezza F., Miura G.I., Palmiter R.D., Sugiura T., Kunos G. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 2001, 410:822-825.
42. Diana M., Melis M., Gessa G.L. Increase in meso-prefrontal dopaminergic activity after stimulation of CB1 receptors by cannabinoids. Eur. J. Neurosci. 1998, 10:2825-2830.
43. Doorduin J., de Vries E.F., Willemsen A.T., de Groot J.C., Dierckx R.A., Klein H.C. Neuroinflammation in schizophrenia-related psychosis: a PET study. J. Nucl. Med. 2009, 50:1801-1807.
44. Dragunow M., Butterworth N., Waldvogel H., Faull R.L., Nicholson L.F. Prolonged expression of Fos-related antigens, Jun B and TrkB in dopamine-denervated striatal neurons. Brain Res. Mol. Brain Res. 1995, 30:393-396.
45. Eggan S.M., Hashimoto T., Lewis D.A. Reduced cortical cannabinoid 1 receptor messenger RNA and protein expression in schizophrenia. Arch. Gen. Psychiatry 2008, 65:772-784.
46. Faber G., Smid H.G., Van Gool A.R., Wunderink L., van den Bosch R.J., Wiersma D. Continued cannabis use and outcome in first-episode psychosis: data from a randomized, open-label, controlled trial. J. Clin. Psychiatry 2012, 73:632-638.
47. Fernandes M., Schabarek A., Coper H., Hill R. Modification of delta9-THC-actions by cannabinol and cannabidiol in the rat. Psychopharmacologia 1974, 38:329-338.
48. Fogaca M.V., Aguiar D.C., Moreira F.A., Guimaraes F.S. The endocannabinoid and endovanilloid systems interact in the rat prelimbic medial prefrontal cortex to control anxiety-like behavior. Neuropharmacology 2012, 63:202-210.
49. Freund T.F., Katona I., Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev. 2003, 83:1017-1066.
50. Fusar-Poli P., Allen P., Bhattacharyya S., Crippa J.A., Mechelli A., Borgwardt S., Martin-Santos R., Seal M.L., O'Carrol C., Atakan Z., Zuardi A.W., McGuire P. Modulation of effective connectivity during emotional processing by Delta 9-tetrahydrocannabinol and cannabidiol. Int. J. Neuropsychopharmacol. 2010, 13:421-432.
51. Fusar-Poli P., Crippa J.A., Bhattacharyya S., Borgwardt S.J., Allen P., Martin-Santos R., Seal M., Surguladze S.A., O'Carrol C., Atakan Z., Zuardi A.W., McGuire P.K. Distinct effects of {delta}9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Arch. Gen. Psychiatry 2009, 66:95-105.
52. Fusar-Poli P., Meyer-Lindenberg A. Striatal presynaptic dopamine in schizophrenia, part i: meta-analysis of Dopamine Active Transporter (DAT) density. Schizophr. Bull. 2012, 39:22-32.
53. Fusar-Poli P., Meyer-Lindenberg A. Striatal presynaptic dopamine in schizophrenia, part ii: meta-analysis of [18F/11C]-DOPA PET studies. Schizophr. Bull. 2012, 39:33-43.
54. Galiegue S., Mary S., Marchand J., Dussossoy D., Carriere D., Carayon P., Bouaboula M., Shire D., Le F.G., Casellas P. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur. J. Biochem. 1995, 232:54-61.
55. Garcia-Gutierrez M.S., Manzanares J. Overexpression of CB2 cannabinoid receptors decreased vulnerability to anxiety and impaired anxiolytic action of alprazolam in mice. J. Psychopharmacol. 2011, 25:111-120.
56. Giuffrida A., Leweke F.M., Gerth C.W., Schreiber D., Koethe D., Faulhaber J., Klosterkotter J., Piomelli D. Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with psychotic symptoms. Neuropsychopharmacology 2004, 29:2108-2114.
57. Glass M., Dragunow M., Faull R.L. Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience 1997, 77:299-318.
58. Gong J.P., Onaivi E.S., Ishiguro H., Liu Q.R., Tagliaferro P.A., Brusco A., Uhl G.R. Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res. 2006, 1071:10-23.
59. Grech A., van O.J., Jones P.B., Lewis S.W., Murray R.M. Cannabis use and outcome of recent onset psychosis. Eur. Psychiatry 2005, 20:349-353.
60. Guimaraes V.M., Zuardi A.W., Del Bel E.A., Guimaraes F.S. Cannabidiol increases Fos expression in the nucleus accumbens but not in the dorsal striatum. Life Sci. 2004, 75:633-638.
61. Gururajan A., Taylor D.A., Malone D.T. Effect of cannabidiol in a MK-801-rodent model of aspects of schizophrenia. Behav. Brain Res. 2011, 222:299-308.
62. Hallak J.E., Dursun S.M., Bosi D.C., de Macedo L.R., hado-de-Sousa J.P., Abrao J., Crippa J.A., McGuire P., Krystal J.H., Baker G.B., Zuardi A.W. The interplay of cannabinoid and NMDA glutamate receptor systems in humans: preliminary evidence of interactive effects of cannabidiol and ketamine in healthy human subjects. Prog. Neuropsychopharmacol. Biol. Psychiatry 2011, 35:198-202.
63. Hampson R.E., Deadwyler S.A. Cannabinoids, hippocampal function and memory. Life Sci. 1999, 65:715-723.
64. Henquet C., Rosa A., Krabbendam L., Papiol S., Fananas L., Drukker M., Ramaekers J.G., van O.J. An experimental study of catechol-o-methyltransferase Val158Met moderation of delta-9-tetrahydrocannabinol-induced effects on psychosis and cognition. Neuropsychopharmacology 2006, 31:2748-2757.
65. Henstridge C.M., Balenga N.A., Kargl J., Andradas C., Brown A.J., Irving A., Sanchez C., Waldhoer M. Minireview: recent developments in the physiology and pathology of the lysophosphatidylinositol-sensitive receptor GPR55. Mol. Endocrinol. 2011, 25:1835-1848.
66. Herkenham M., Groen B.G., Lynn A.B., De Costa B.R., Richfield E.K. Neuronal localization of cannabinoid receptors and second messengers in mutant mouse cerebellum. Brain Res. 1991, 552:301-310.
67. Hermann D., Schneider M. Potential protective effects of cannabidiol on neuroanatomical alterations in cannabis users and psychosis: a critical review. Curr. Pharm. Des. 2012, 18:4897-4905.
68. Hill M.N., Patel S., Campolongo P., Tasker J.G., Wotjak C.T., Bains J.S. Functional interactions between stress and the endocannabinoid system: from synaptic signaling to behavioral output. J. Neurosci. 2010, 30:14980-14986.
69. Ho B.C., Wassink T.H., Ziebell S., Andreasen N.C. Cannabinoid receptor 1 gene polymorphisms and marijuana misuse interactions on white matter and cognitive deficits in schizophrenia. Schizophr. Res. 2011, 128:66-75.
70. Howes O.D., Kapur S. The dopamine hypothesis of schizophrenia: version III-the final common pathway. Schizophr. Bull. 2009, 35:549-562.
71. Howlett A.C. The cannabinoid receptors. Prostaglandins Other Lipid Mediat. 2002, 68-69:619-631.
72. Howlett A.C., Blume L.C., Dalton G.D. CB(1) cannabinoid receptors and their associated proteins. Curr. Med. Chem. 2010, 17:1382-1393.
73. Howlett A.C., Breivogel C.S., Childers S.R., Deadwyler S.A., Hampson R.E., Porrino L.J. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology 2004, 47(1):345-358.
74. Huang S.M., Bisogno T., Trevisani M., Al-Hayani A., De P.L., Fezza F., Tognetto M., Petros T.J., Krey J.F., Chu C.J., Miller J.D., Davies S.N., Geppetti P., Walker J.M., Di M.V. An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proc. Natl. Acad. Sci. USA 2002, (99):8400-8405.
75. Huestis M.A., Gorelick D.A., Heishman S.J., Preston K.L., Nelson R.A., Moolchan E.T., Frank R.A. Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716. Arch. Gen. Psychiatry 2001, 58:322-328.
76. Ignatowska-Jankowska B., Jankowski M., Glac W., Swiergel A.H. Cannabidiol-induced lymphopenia does not involve NKT and NK cells. J. Physiol. Pharmacol. 2009, 60(3):99-103.
77. Ilan A.B., Gevins A., Coleman M., ElSohly M.A., de W.H. Neurophysiological and subjective profile of marijuana with varying concentrations of cannabinoids. Behav. Pharmacol. 2005, 16:487-496.
78. Ishiguro H., Horiuchi Y., Ishikawa M., Koga M., Imai K., Suzuki Y., Morikawa M., Inada T., Watanabe Y., Takahashi M., Someya T., Ujike H., Iwata N., Ozaki N., Onaivi E.S., Kunugi H., Sasaki T., Itokawa M., Arai M., Niizato K., Iritani S., Naka I., Ohashi J., Kakita A., Takahashi H., Nawa H., Arinami T. Brain cannabinoid CB2 receptor in schizophrenia. Biol. Psychiatry 2010, 67:974-982.
79. Jenko K.J., Hirvonen J., Henter I.D., Anderson K.B., Zoghbi S.S., Hyde T.M., ep-Soboslay A., Innis R.B., Kleinman J.E. Binding of a tritiated inverse agonist to cannabinoid CB1 receptors is increased in patients with schizophrenia. Schizophr. Res. 2012, 141:185-188.
80. Juckel G., Roser P., Nadulski T., Stadelmann A.M., Gallinat J. Acute effects of Delta9-tetrahydrocannabinol and standardized cannabis extract on the auditory evoked mismatch negativity. Schizophr. Res. 2007, 97:109-117.
81. Kaplan B.L., Springs A.E., Kaminski N.E. The profile of immune modulation by cannabidiol (CBD) involves deregulation of nuclear factor of activated T cells (NFAT). Biochem. Pharmacol. 2008, 76:726-737.
82. Karniol I.G., Shirakawa I., Kasinski N., Pfeferman A., Carlini E.A. Cannabidiol interferes with the effects of delta 9-tetrahydrocannabinol in man. Eur. J. Pharmacol. 1974, 28:172-177.
83. Kay S.R., Fiszbein A., Opler L.A. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 1987, 13:261-276.
84. Klein T.W., Newton C.A., Friedman H. Cannabinoids and the immune system. Pain Res. Manag. 2001, 6:95-101.
85. Koethe D., Giuffrida A., Schreiber D., Hellmich M., Schultze-Lutter F., Ruhrmann S., Klosterkotter J., Piomelli D., Leweke F.M. Anandamide elevation in cerebrospinal fluid in initial prodromal states of psychosis. Br. J. Psychiatry 2009, 194:371-372.
86. Kozela E., Lev N., Kaushansky N., Eilam R., Rimmerman N., Levy R., Ben-Nun A., Juknat A., Vogel Z. Cannabidiol inhibits pathogenic T cells, decreases spinal microglial activation and ameliorates multiple sclerosis-like disease in C57BL/6 mice. Br. J. Pharmacol. 2011, 163:1507-1519.
87. Kozela E., Pietr M., Juknat A., Rimmerman N., Levy R., Vogel Z. Cannabinoids Delta(9)-tetrahydrocannabinol and cannabidiol differentially inhibit the lipopolysaccharide-activated NF-kappaB and interferon-beta/STAT proinflammatory pathways in BV-2 microglial cells. J. Biol. Chem. 2010, 285:1616-1626.
88. Kuepper R., Morrison P.D., van O.J., Murray R.M., Kenis G., Henquet C. Does dopamine mediate the psychosis-inducing effects of cannabis? A review and integration of findings across disciplines. Schizophr. Res. 2010, 121:107-117.
89. Leweke F.M., Giuffrida A., Koethe D., Schreiber D., Nolden B.M., Kranaster L., Neatby M.A., Schneider M., Gerth C.W., Hellmich M., Klosterkotter J., Piomelli D. Anandamide levels in cerebrospinal fluid of first-episode schizophrenic patients: impact of cannabis use. Schizophr. Res. 2007, 94:29-36.
90. Leweke F.M., Giuffrida A., Wurster U., Emrich H.M., Piomelli D. Elevated endogenous cannabinoids in schizophrenia. Neuroreport 1999, 10:1665-1669.
91. Leweke F.M., Piomelli D., Pahlisch F., Muhl D., Gerth C.W., Hoyer C., Klosterkotter J., Hellmich M., Koethe D. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl. Psychiatry 2012, 2:e94.
92. Leweke F.M., Schneider U., Radwan M., Schmidt E., Emrich H.M. Different effects of nabilone and cannabidiol on binocular depth inversion in Man. Pharmacol. Biochem. Behav. 2000, 66:175-181.
93. Linszen D.H., Dingemans P.M., Lenior M.E. Cannabis abuse and the course of recent-onset schizophrenic disorders. Arch. Gen. Psychiatry 1994, 51:273-279.
94. Lipska B.K., Weinberger D.R. To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology 2000, 23:223-239.
95. Long L.E., Chesworth R., Huang X.F., McGregor I.S., Arnold J.C., Karl T. A behavioural comparison of acute and chronic Delta9-tetrahydrocannabinol and cannabidiol in C57BL/6JArc mice. Int. J. Neuropsychopharmacol. 2010, 13:861-876.
96. Long L.E., Malone D.T., Taylor D.A. Cannabidiol reverses MK-801-induced disruption of prepulse inhibition in mice. Neuropsychopharmacology 2006, 31:795-803.
97. Macleod J., Oakes R., Copello A., Crome I., Egger M., Hickman M., Oppenkowski T., Stokes-Lampard H., Davey S.G. Psychological and social sequelae of cannabis and other illicit drug use by young people: a systematic review of longitudinal, general population studies. Lancet 2004, 363:1579-1588.
98. Mailleux P., Parmentier M., Vanderhaeghen J.J. Distribution of cannabinoid receptor messenger RNA in the human brain: an in situ hybridization histochemistry with oligonucleotides. Neurosci. Lett. 1992, 143:200-204.
99. Malone D.T., Jongejan D., Taylor D.A. Cannabidiol reverses the reduction in social interaction produced by low dose Delta(9)-tetrahydrocannabinol in rats. Pharmacol. Biochem. Behav. 2009, 93:91-96.
100. Manrique-Garcia E., Zammit S., Dalman C., Hemmingsson T., Andreasson S., Allebeck P. Cannabis, schizophrenia and other non-affective psychoses: 35 years of follow-up of a population-based cohort. Psychol. Med. 2012, 42:1321-1328.
101. Marco E.M., Garcia-Gutierrez M.S., Bermudez-Silva F.J., Moreira F.A., Guimaraes F., Manzanares J., Viveros M.P. Endocannabinoid system and psychiatry: in search of a neurobiological basis for detrimental and potential therapeutic effects. Front. Behav. Neurosci. 2011, 5:63.
102. Martin-Moreno A.M., Reigada D., Ramirez B.G., Mechoulam R., Innamorato N., Cuadrado A., de Ceballos M.L. Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer's disease. Mol. Pharmacol. 2011, 79:964-973.
103. Martinez-Gras I., Hoenicka J., Ponce G., Rodriguez-Jimenez R., Jimenez-Arriero M.A., Perez-Hernandez E., Ampuero I., Ramos-Atance J.A., Palomo T., Rubio G. (AAT)n repeat in the cannabinoid receptor gene, CNR1: association with schizophrenia in a Spanish population. Eur. Arch. Psychiatry Clin. Neurosci. 2006, 256:437-441.
104. Matochik J.A., Eldreth D.A., Cadet J.L., Bolla K.I. Altered brain tissue composition in heavy marijuana users. Drug Alcohol Depend. 2005, 77:23-30.
105. Matsuyama S.S., Fu T.K. In vivo cytogenetic effects of cannabinoids. J. Clin. Psychopharmacol. 1981, 1:135-140.
106. McGrath J., Saha S., Chant D., Welham J. Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol. Rev. 2008, 30:67-76.
107. Mechoulam R., Peters M., Murillo-Rodriguez E., Hanus L.O. Cannabidiol-recent advances. Chem. Biodivers. 2007, 4:1678-1692.
108. Mechoulam R., Shani A., Edery H., Grunfeld Y. Chemical basis of hashish activity. Science 1970, 169:611-612.
109. Minozzi S., Davoli M., Bargagli A.M., Amato L., Vecchi S., Perucci C.A. An overview of systematic reviews on cannabis and psychosis: discussing apparently conflicting results. Drug Alcohol Rev. 2010, 29:304-317.
110. Moore T.H., Zammit S., Lingford-Hughes A., Barnes T.R., Jones P.B., Burke M., Lewis G. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet 2007, 370:319-328.
111. Moreira F.A., Guimaraes F.S. Cannabidiol inhibits the hyperlocomotion induced by psychotomimetic drugs in mice. Eur. J. Pharmacol. 2005, 512:199-205.
112. Morgan C.J., Curran H.V. Effects of cannabidiol on schizophrenia-like symptoms in people who use cannabis. Br. J. Psychiatry 2008, 192:306-307.
113. Morgan C.J., Freeman T.P., Schafer G.L., Curran H.V. Cannabidiol attenuates the appetitive effects of Delta(9)-tetrahydrocannabinol in humans smoking their chosen cannabis. Neuropsychopharmacology 2010.
114. Morgan C.J., Gardener C., Schafer G., Swan S., Demarchi C., Freeman T.P., Warrington P., Rupasinghe I., Ramoutar A., Tan N., Wingham G., Lewis S., Curran H.V. Sub-chronic impact of cannabinoids in street cannabis on cognition, psychotic-like symptoms and psychological well-being. Psychol. Med. 2011, 29:1-10.
115. Morgan C.J., Schafer G., Freeman T.P., Curran H.V. Impact of cannabidiol on the acute memory and psychotomimetic effects of smoked cannabis: naturalistic study: naturalistic study [corrected]. Br. J. Psychiatry 2010, 197:285-290.
116. Morrison P.D., Nottage J., Stone J.M., Bhattacharyya S., Tunstall N., Brenneisen R., Holt D., Wilson D., Sumich A., McGuire P., Murray R.M., Kapur S., Ffytche D.H. Disruption of frontal θ coherence by δ9-tetrahydrocannabinol is associated with positive psychotic symptoms. Neuropsychopharmacology 2011, 36:827-836.
117. Muller N., Riedel M., Gruber R., Ackenheil M., Schwarz M.J. The immune system and schizophrenia. An integrative view. Ann. N. Y. Acad. Sci. 2000, 917:456-467.
118. Munro S., Thomas K.L., bu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993, 365:61-65.
119. Myles N., Newall H., Nielssen O., Large M. The association between cannabis use and earlier age at onset of schizophrenia and other psychoses: meta-analysis of possible confounding factors. Curr. Pharm. Des. 2012, 18:5055-5069.
120. Newell K.A., Deng C., Huang X.F. Increased cannabinoid receptor density in the posterior cingulate cortex in schizophrenia. Exp. Brain Res. 2006, 172:556-560.
121. 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, 1074:514-536.
122. Perez-Reyes M., Timmons M.C., Davis K.H., Wall E.M. A comparison of the pharmacological activity in man of intravenously administered delta9-tetrahydrocannabinol, cannabinol, and cannabidiol. Experientia 1973, 29:1368-1369.
123. Pertwee R.G. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br. J. Pharmacol. 2008, 153:199-215.
124. Pertwee R.G., Thomas A., Stevenson L.A., Ross R.A., Varvel S.A., Lichtman A.H., Martin B.R., Razdan R.K. The psychoactive plant cannabinoid, Delta9-tetrahydrocannabinol, is antagonized by Delta8- and Delta9-tetrahydrocannabivarin in mice in vivo. Br. J. Pharmacol. 2007, 150:586-594.
125. Pijlman F.T., Rigter S.M., Hoek J., Goldschmidt H.M., Niesink R.J. Strong increase in total delta-THC in cannabis preparations sold in Dutch coffee shops. Addict. Biol. 2005, 10:171-180.
126. Potter D.J., Clark P., Brown M.B. Potency of delta 9-THC and other cannabinoids in cannabis in England in 2005: implications for psychoactivity and pharmacology. J. Forensic Sci. 2008, 53:90-94.
127. Rais M., Cahn W., Van H.N., Schnack H., Caspers E., Hulshoff P.H., Kahn R. Excessive brain volume loss over time in cannabis-using first-episode schizophrenia patients. Am. J. Psychiatry 2008, 165:490-496.
128. Rapp C., Bugra H., Riecher-Rossler A., Tamagni C., Borgwardt S. Effects of cannabis use on human brain structure in psychosis: a systematic review combining in vivo structural neuroimaging and post mortem studies. Curr. Pharm. Des. 2012, 18:5070-5080.
129. Robertson G.S., Fibiger H.C. Neuroleptics increase c-fos expression in the forebrain: contrasting effects of haloperidol and clozapine. Neuroscience 1992, 46:315-328.
130. Rosenkrantz H., Fleischman R.W., Grant R.J. Toxicity of short-term administration of cannabinoids to rhesus monkeys. Toxicol. Appl. Pharmacol. 1981, 58:118-131.
131. Roser P., Juckel G., Rentzsch J., Nadulski T., Gallinat J., Stadelmann A.M. Effects of acute oral Delta9-tetrahydrocannabinol and standardized cannabis extract on the auditory P300 event-related potential in healthy volunteers. Eur. Neuropsychopharmacol. 2008, 18:569-577.
132. Rottanburg D., Robins A.H., Ben-Arie O., Teggin A., Elk R. Cannabis-associated psychosis with hypomanic features. Lancet 1982, 2:1364-1366.
133. Sanchez C., Galve-Roperh I., Canova C., Brachet P., Guzman M. Delta9-tetrahydrocannabinol induces apoptosis in C6 glioma cells. FEBS Lett. 1998, 436:6-10.
134. Schneider U., Borsutzky M., Seifert J., Leweke F.M., Huber T.J., Rollnik J.D., Emrich H.M. Reduced binocular depth inversion in schizophrenic patients. Schizophr. Res. 2002, 53:101-108.
135. Schubart C.D., Sommer I.E., van Gastel W.A., Goetgebuer R.L., Kahn R.S., Boks M.P. Cannabis with high cannabidiol content is associated with fewer psychotic experiences. Schizophr. Res. 2011, 130:216-221.
136. Schubart C.D., van Gastel W.A., Breetvelt E.J., Beetz S.L., Ophoff R.A., Sommer I.E., Kahn R.S., Boks M.P. Cannabis use at a young age is associated with psychotic experiences. Psychol. Med. 2010, 41:1301-1310.
137. Skinner R., Conlon L., Gibbons D., McDonald C. Cannabis use and non-clinical dimensions of psychosis in university students presenting to primary care. Acta Psychiatr. Scand. 2010, 123:21-27.
138. Stadelmann A.M., Juckel G., Arning L., Gallinat J., Epplen J.T., Roser P. Association between a cannabinoid receptor gene (CNR1) polymorphism and cannabinoid-induced alterations of the auditory event-related P300 potential. Neurosci. Lett. 2011, 496:60-64.
139. Starowicz K., Cristino L., Di M.V. TRPV1 receptors in the central nervous system: potential for previously unforeseen therapeutic applications. Curr. Pharm. Des. 2008, 14:42-54.
140. Stefanis N.C., Delespaul P., Henquet C., Bakoula C., Stefanis C.N., van O.J. Early adolescent cannabis exposure and positive and negative dimensions of psychosis. Addiction 2004, 99:1333-1341.
141. Stefansson H., Ophoff R.A., Steinberg S., Andreassen O.A., Cichon S., Rujescu D., Werge T., Pietilainen O.P., Mors O., Mortensen P.B., Sigurdsson E., Gustafsson O., Nyegaard M., Tuulio-Henriksson A., Ingason A., Hansen T., Suvisaari J., Lonnqvist J., Paunio T., Borglum A.D., Hartmann A., Fink-Jensen A., Nordentoft M., Hougaard D., Norgaard-Pedersen B., Bottcher Y., Olesen J., Breuer R., Moller H.J., Giegling I., Rasmussen H.B., Timm S., Mattheisen M., Bitter I., Rethelyi J.M., Magnusdottir B.B., Sigmundsson T., Olason P., Masson G., Gulcher J.R., Haraldsson M., Fossdal R., Thorgeirsson T.E., Thorsteinsdottir U., Ruggeri M., Tosato S., Franke B., Strengman E., Kiemeney L.A., Melle I., Djurovic S., Abramova L., Kaleda V., Sanjuan J., de Frutos R., Bramon E., Vassos E., Fraser G., Ettinger U., Picchioni M., Walker N., Toulopoulou T., Need A.C., Ge D., Yoon J.L., Shianna K.V., Freimer N.B., Cantor R.M., Murray R., Kong A., Golimbet V., Carracedo A., Arango C., Costas J., Jonsson E.G., Terenius L., Agartz I., Petursson H., Nothen M.M., Rietschel M., Matthews P.M., Muglia P., Peltonen L., St C.D., Goldstein D.B., Stefansson K., Collier D.A. Common variants conferring risk of schizophrenia. Nature 2009, 460:744-747.
142. Stokes P.R., Mehta M.A., Curran H.V., Breen G., Grasby P.M. Can recreational doses of THC produce significant dopamine release in the human striatum?. Neuroimage 2009, 48:186-190.
143. Stone J.M., Morrison P.D., Brugger S., Nottage J., Bhattacharyya S., Sumich A., Wilson D., Tunstall N., Feilding A., Brenneisen R., McGuire P., Murray R.M., Ffytche D.H. Communication breakdown: delta-9 tetrahydrocannabinol effects on pre-speech neural coherence. Mol. Psychiatry. 2012, 17:568-569.
144. Tanda G., Pontieri F.E., Di C.G. Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism. Science 1997, 276:2048-2050.
145. Thomas A., Baillie G.L., Phillips A.M., Razdan R.K., Ross R.A., Pertwee R.G. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br. J. Pharmacol. 2007, 150:613-623.
146. Tsai S.J., Wang Y.C., Hong C.J. Association study of a cannabinoid receptor gene (CNR1) polymorphism and schizophrenia. Psychiatr. Genet. 2000, 10:149-151.
147. Ueda N., Tsuboi K., Uyama T., Ohnishi T. Biosynthesis and degradation of the endocannabinoid 2-arachidonoylglycerol. Biofactors 2011, 37:1-7.
148. Ujike H., Takaki M., Nakata K., Tanaka Y., Takeda T., Kodama M., Fujiwara Y., Sakai A., Kuroda S. CNR1, central cannabinoid receptor gene, associated with susceptibility to hebephrenic schizophrenia. Mol. Psychiatry 2002, 7:515-518.
149. Umathe S.N., Manna S.S., Jain N.S. Endocannabinoid analogues exacerbate marble-burying behavior in mice via TRPV1 receptor. Neuropharmacology 2012, 62:2024-2033.
150. Umbricht D., Krljes S. Mismatch negativity in schizophrenia: a meta-analysis. Schizophr. Res. 2005, 76:1-23.
151. Urigüen L., Garcia-Fuster M.J., Callado L.F., Morentin B., La H.R., Casado V., Lluis C., Franco R., Garcia-Sevilla J.A., Meana J.J. Immunodensity and mRNA expression of A2A adenosine, D2 dopamine, and CB1 cannabinoid receptors in postmortem frontal cortex of subjects with schizophrenia: effect of antipsychotic treatment. Psychopharmacology (Berlin) 2009, 206:313-324.
152. van Berckel B.N., Bossong M.G., Boellaard R., Kloet R., Schuitemaker A., Caspers E., Luurtsema G., Windhorst A.D., Cahn W., Lammertsma A.A., Kahn R.S. Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study. Biol. Psychiatry 2008, 64:820-822.
153. van Gastel W.A., Wigman J.T., Monshouwer K., Kahn R.S., van O.J., Boks M.P., Vollebergh W.A. Cannabis use and subclinical positive psychotic experiences in early adolescence: findings from a Dutch survey. Addiction 2012, 107:381-387.
154. van Os J., Bak M., Hanssen M., Bijl R.V., de G.R., Verdoux H. Cannabis use and psychosis: a longitudinal population-based study. Am. J. Epidemiol. 2002, 156:319-327.
155. van Os J., Kapur S. Schizophrenia. Lancet 2009, 374:635-645.
156. 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, 310:329-332.
157. van Winkel R. Family-based analysis of genetic variation underlying psychosis-inducing effects of cannabis: sibling analysis and proband follow-up. Arch. Gen. Psychiatry 2011, 68:148-157.
158. Verrico C.D., Jentsch J.D., Roth R.H., Taylor J.R. Repeated, intermittent delta(9)-tetrahydrocannabinol administration to rats impairs acquisition and performance of a test of visuospatial divided attention. Neuropsychopharmacology 2004, 29:522-529.
159. Waksman Y., Olson J.M., Carlisle S.J., Cabral G.A. The central cannabinoid receptor (CB1) mediates inhibition of nitric oxide production by rat microglial cells. J. Pharmacol. Exp. Ther. 1999, 288:1357-1366.
160. Walter L., Franklin A., Witting A., Wade C., Xie Y., Kunos G., Mackie K., Stella N. Nonpsychotropic cannabinoid receptors regulate microglial cell migration. J. Neurosci. 2003, 23:1398-1405.
161. Winton-Brown T.T., Allen P., Bhattacharyya S., Borgwardt S.J., Fusar-Poli P., Crippa J.A., Seal M.L., Martin-Santos R., Ffytche D., Zuardi A.W., Atakan Z., McGuire P.K. Modulation of auditory and visual processing by delta-9-tetrahydrocannabinol and cannabidiol: an FMRI study. Neuropsychopharmacology 2011, 36:1340-1348.
162. Wong D.F., Kuwabara H., Horti A.G., Raymont V., Brasic J., Guevara M., Ye W., Dannals R.F., Ravert H.T., Nandi A., Rahmim A., Ming J.E., Grachev I., Roy C., Cascella N. Quantification of cerebral cannabinoid receptors subtype 1 (CB1) in healthy subjects and schizophrenia by the novel PET radioligand [11C]OMAR. Neuroimage 2010, 52:1505-1513.
163. Yücel M., Solowij N., Respondek C., Whittle S., Fornito A., Pantelis C., Lubman D.I. Regional brain abnormalities associated with long-term heavy cannabis use. Arch. Gen. Psychiatry 2008, 65:694-701.
164. Zammit S., Allebeck P., Andreasson S., Lundberg I., Lewis G. Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study. Br. Med. J. 2002, 325:1199.
165. Zavitsanou K., Garrick T., Huang X.F. Selective antagonist [3H]SR141716A binding to cannabinoid CB1 receptors is increased in the anterior cingulate cortex in schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 2004, 28:355-360.
166. Zuardi A., Crippa J., Dursun S., Morais S., Vilela J., Sanches R., Hallak J. Cannabidiol was ineffective for manic episode of bipolar affective disorder. J. Psychopharmacol. 2010, 24:135-137.
167. Zuardi A.W., Crippa J.A., Hallak J.E., Pinto J.P., Chagas M.H., Rodrigues G.G., Dursun S.M., Tumas V. Cannabidiol for the treatment of psychosis in Parkinson's disease. J. Psychopharmacol. 2009, 23:979-983.
168. Zuardi A.W., Hallak J.E., Dursun S.M., Morais S.L., Sanches R.F., Musty R.E., Crippa J.A. Cannabidiol monotherapy for treatment-resistant schizophrenia. J. Psychopharmacol. 2006, 20:683-686.
169. Zuardi A.W., Loureiro S.R., Rodrigues C.R. Reliability, validity and factorial dimensions of the interactive observation scale for psychiatric inpatients. Acta Psychiatr. Scand. 1995, 91:247-251.
170. Zuardi A.W., Morais S.L., Guimaraes F.S., Mechoulam R. Antipsychotic effect of cannabidiol. J. Clin. Psychiatry 1995, 56:485-486.
171. Zuardi A.W., Rodrigues J.A., Cunha J.M. Effects of cannabidiol in animal models predictive of antipsychotic activity. Psychopharmacology (Berlin) 1991, 104:260-264.
172. Zuardi A.W., Shirakawa I., Finkelfarb E., Karniol I.G. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology (Berlin) 1982, 76:245-250.
173. Zuardi A.W., Crippa J.A., Hallak J.E., Bhattacharyya S., Atakan Z., Martin-Santos R., McGuire P.K., Guimarães F.S. A critical review of the antipsychotic effects of cannabidiol: 30 years of a translational investigation. Curr. Pharm. Des. 2012, 18:5131-5140.