Cannabidiol increases survival and promotes rescue of cognitive function in a murine model of cerebral malaria

Neuroscience

Volumn 289, Issue , 2015, Pages 166-180

  Campos, A C ^a,b   Brant, F ^a   Miranda, A S ^a   Machado, F S ^a   Teixeira, A L ^a  

^a FEDERAL UNIVERSITY OF MINAS GERAIS   (Brazil)

^b UNIVERSITY OF SÃO PAULO   (Brazil)

Author keywords

Brain derived neurotrophic factor; Cannabidiol; Cerebral malaria; Cytokines; Inflammation

Indexed keywords

ARTESUNATE; BRAIN DERIVED NEUROTROPHIC FACTOR; CANNABIDIOL; GAMMA INTERFERON; INTERLEUKIN 10; INTERLEUKIN 2; INTERLEUKIN 4; INTERLEUKIN 6; NERVE GROWTH FACTOR; TUMOR NECROSIS FACTOR ALPHA; ANTIMALARIAL AGENT; ARTEMISININ DERIVATIVE; NEUROPROTECTIVE AGENT;

AMNESIA; ANIMAL BEHAVIOR; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIINFLAMMATORY ACTIVITY; ARTICLE; BRAIN MALARIA; COGNITION; CONTROLLED STUDY; ELEVATED PLUS MAZE TEST; FEMALE; HIPPOCAMPUS; MORRIS WATER MAZE TEST; MOUSE; NEUROPROTECTION; NONHUMAN; NOVEL OBJECT RECOGNITION TEST; OPEN FIELD TEST; PREFRONTAL CORTEX; PROTEIN EXPRESSION; REPEATED DRUG DOSE; SINGLE DRUG DOSE; SURVIVAL RATE; UPREGULATION; ANIMAL; ANXIETY; C57BL MOUSE; DISEASE MODEL; DRUG COMBINATION; DRUG EFFECTS; MALARIA, CEREBRAL; MEMORY DISORDERS; METABOLISM; PATHOPHYSIOLOGY; PHYSIOLOGY; PLASMODIUM BERGHEI; PSYCHOLOGY; SURVIVAL; TREATMENT OUTCOME;

ANIMALS; ANTIMALARIALS; ANXIETY; ARTEMISININS; BRAIN-DERIVED NEUROTROPHIC FACTOR; CANNABIDIOL; COGNITION; DISEASE MODELS, ANIMAL; DRUG THERAPY, COMBINATION; FEMALE; HIPPOCAMPUS; MALARIA, CEREBRAL; MEMORY DISORDERS; MICE, INBRED C57BL; NERVE GROWTH FACTOR; NEUROPROTECTIVE AGENTS; PLASMODIUM BERGHEI; PREFRONTAL CORTEX; SURVIVAL ANALYSIS; TREATMENT OUTCOME;

EID: 84921854170     PISSN: 03064522     EISSN: 18737544     Source Type: Journal    
DOI: 10.1016/j.neuroscience.2014.12.051     Document Type: Article

References (85)

1. Alvarez F.J., Lafuente H., Rey-Santano M.C., Mielgo V.E., Gastiasoro E., Rueda M., Pertwee R.G., Castillo A.I., Romero J., Martinez-Orgado J. Cannabidiol reduces brain damage and improves functional recovery after acute hypoxia-ischemia in newborn pigs. Pediatr Res 2008, 64:653-658.
2. Armah H., Wired E.K., Dodoo A.K., Adjei A.A., Tettey Y., Gyasi R. Cytokines and adhesion molecules expression in the brain in human cerebral malaria. Int J Environ Res Public Health 2005, 2:123-131.
3. Atzori M., Garcia-Oscos F., Mendez J.A. Role of IL-6 in the etiology of hyperexcitable neuropsychiatric conditions: experimental evidence and therapeutic implications. Future Med Chem 2012, 4:2177-2192.
4. Barichello T., Belarmino E., Comim C.M., Cipriano A.L., Generoso J.S., Savi G.D., Stertz L., Kapczinski F., Quevedo J. Correlation between behavioral deficits and decreased brain-derived neurotrophic factor in neonatal meningitis. J Neuroimmunol 2010, 223:73-76.
5. 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.
6. Bechara R.G., Kelly A.M. Exercise improves object recognition memory and induces BDNF expression and cell proliferation in cognitively enriched rats. Behav Brain Res 2013, 245:96-100.
7. Berendt A.R., Ferguson D.J., Gardner J., Turner G., Rowe A., McCormick C., Roberts D., Craig A., Pinches R., Elford B.C., et al. Molecular mechanisms of sequestration in malaria. Parasitology 1994, 108(Suppl):S19-S28.
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. Bevins R.A., Besheer J. Object recognition in rats and mice: a one-trial non-matching-to-sample learning task to study 'recognition memory'. Nat Protoc 2006, 1:1306-1311.
10. Bradford M.M. A Rapid and Sensitive Method for the Quantitation of Microgram Quantities of Protein Utilizing the Principle of Protein-Dye Binding. Analytical Biochemistry 1976, 72:248-254.
11. Campos A.C., Guimaraes F.S. Evidence for a potential role for TRPV1 receptors in the dorsolateral periaqueductal gray in the attenuation of the anxiolytic effects of cannabinoids. Prog Neuropsychopharmacol Biol Psychiatry 2009, 33:1517-1521.
12. Campos A.C., Guimaraes F.S. Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology 2008, 199:223-230.
13. Campos A.C., Ferreira F.R., Guimaraes F.S. Cannabidiol blocks long-lasting behavioral consequences of predator threat stress: possible involvement of 5HT1A receptors. J Psychiatr Res 2012, 46:1501-1510.
14. Campos A.C., Moreira F.A., Gomes F.V., Del Bel E.A., Guimaraes F.S. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos Trans R Soc Lond B Biol Sci 2012, 367:3364-3378.
15. Campos A.C., Ortega Z., Palazuelos J., Fogaca M.V., Aguiar D.C., Diaz-Alonso J., Ortega-Gutierrez S., Vazquez-Villa H., Moreira F.A., Guzman M., Galve-Roperh I., Guimaraes F.S. Int J Neuropsychopharmacol 2013, 16:1407-1419.
16. Campos A.C., Vaz G.N., Saito V.M., Teixeira A.L. Further evidence for the role of interferon-gamma on anxiety- and depressive-like behaviors: involvement of hippocampal neurogenesis and NGF production. Neurosci Lett 2014, 78C:100-105.
17. Carlino D., De Vanna M., Tongiorgi E. Is altered BDNF biosynthesis a general feature in patients with cognitive dysfunctions?. Neuroscientist 2013, 19:345-353.
18. Carroll R.W., Wainwright M.S., Kim K.Y., Kidambi T., Gomez N.D., Taylor T., Haldar K. A rapid murine coma and behavior scale for quantitative assessment of murine cerebral malaria. PLoS One 2010, 5:e13124.
19. Carter J.A., Mung'ala-Odera V., Neville B.G., Murira G., Mturi N., Musumba C., Newton C.R. Persistent neurocognitive impairments associated with severe falciparum malaria in Kenyan children. J Neurol Neurosurg Psychiatry 2005, 76:476-481.
20. Chen J., Song Y., Yang J., et al. The contribution of TNF-alpha in the amygdala to anxiety in mice with persistent inflammatory pain. Neurosci Lett 2013, 541:275-280.
21. Clark I.A., Rockett K.A. Sequestration, cytokines, and malaria pathology. Int J Parasitol 1994, 24:165-166.
22. Clemmer L., Martins Y.C., Zanini G.M., Frangos J.A., Carvalho L.J. Artemether and artesunate show the highest efficacies in rescuing mice with late-stage cerebral malaria and rapidly decrease leukocyte accumulation in the brain. Antimicrob Agents Chemother 2011, 55:1383-1390.
23. Comim C.M., Reis P.A., Frutuoso V.S., Fries G.R., Fraga D.B., Kapczinski F., Zugno A.I, Barichello T., Quevedo J., Castro-Faria-Neto H.C. Effects of experimental cerebral malaria in memory, brain-derived neurotrophic factor and acetylcholinesterase activity [correction for activity] in the hippocampus of survivor mice. Neurosci Lett 2012, 523:104-107.
24. Crawley J., Smith S., Muthinji P., Marsh K., Kirkham F. Electroencephalographic and clinical features of cerebral malaria. Arch Dis Child 2001, 84:247-253.
25. Dai M., Freeman B., Shikani H.J., Bruno F.P., Collado J.E., Macias R., Reznik S.E., Davies P., Spray D.C., Tanowitz H.B., Weiss L.M., Desruisseaux M.S. Altered regulation of Akt signaling with murine cerebral malaria, effects on long-term neuro-cognitive function, restoration with lithium treatment. PLoS One 2012, 7:e44117.
26. Dai M., Reznik S.E., Spray D.C., Weiss L.M., Tanowitz H.B., Gulinello M., Desruisseaux M.S. Persistent cognitive and motor deficits after successful antimalarial treatment in murine cerebral malaria. Microbes Infect. 2010, 12:1198-1207.
27. Dao N.V., Cuong B.T., Ngoa N.D., Thuy le T.T., The N.D., Duy D., Dai B., Thanh N.X., Chavchich M., Rieckmann K.H., Edstein M.D. Vivax malaria: preliminary observations following a shorter course of treatment with artesunate plus primaquine. Trans R Soc Trop Med Hyg 2007, 101:534-539.
28. de Miranda A.S., Brant F., Machado F.S., Rachid M.A., Teixeira A.L. Improving cognitive outcome in cerebral malaria: insights from clinical and experimental research. Cent Nerv Syst Agents Med Chem 2011, 11:285-295.
29. de Miranda A.S., Lacerda-Queiroz N., de Carvalho Vilela M., Rodrigues D.H., Rachid M.A., Quevedo J., Teixeira A.L. Anxiety-like behavior and proinflammatory cytokine levels in the brain of C57BL/6 mice infected with Plasmodium berghei (strain ANKA). Neurosci Lett 2011, 491:202-206.
30. de Souza J.B., Hafalla J.C., Riley E.M., Couper K.N. Cerebral malaria: why experimental murine models are required to understand the pathogenesis of disease. Parasitology 2010, 137:755-772.
31. 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.
32. Desruisseaux M.S., Gulinello M., Smith D.N., Lee S.C., Tsuji M., Weiss L.M., Spray D.C., Tanowitz H.B. Cognitive dysfunction in mice infected with Plasmodium berghei strain ANKA. J Infect Dis 2008, 197:1621-1627.
33. Dincheva I., Glatt C.E., Lee F.S. Impact of the BDNF Val66Met polymorphism on cognition: implications for behavioral genetics. Neuroscientist 2012, 18:439-451.
34. Dondorp A., Nosten F., Stepniewska K., Day N., White N. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 2005, 366:717-725. South East Asian Quinine Artesunate Malaria Trial G.
35. Erdman L.K., Dhabangi A., Musoke C., Conroy A.L., Hawkes M., Higgins S., Rajwans N., Wolofsky K.T., Streiner D.L., Liles W.C., Cserti-Gazdewich C.M., Kain K.C. Combinations of host biomarkers predict mortality among Ugandan children with severe malaria: a retrospective case-control study. PLoS One 2011, 6:e17440.
36. Esposito G., De Filippis D., Maiuri M.C., De Stefano D., Carnuccio R., Iuvone T. Cannabidiol inhibits inducible nitric oxide synthase protein expression and nitric oxide production in beta-amyloid stimulated PC12 neurons through p38 MAP kinase and NF-kappaB involvement. Neurosci Lett 2006, 399:91-95.
37. Esposito G., Scuderi C., Valenza M., Togna G.I., Latina V., De Filippis D., Cipriano M., Carratu M.R., Iuvone T., Steardo L. Cannabidiol reduces Abeta-induced neuroinflammation and promotes hippocampal neurogenesis through PPARgamma involvement. PLoS One 2011, 6:e28668.
38. Fernandez-Ruiz J., Sagredo O., Pazos M.R., Garcia C., Pertwee R., Mechoulam R., Martinez-Orgado J. Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid?. Br J Clin Pharmacol 2013, 75:323-333.
39. Fogaca M.V., Reis F.M., Campos A.C., Guimaraes F.S. Effects of intra-prelimbic prefrontal cortex injection of cannabidiol on anxiety-like behavior: involvement of 5HT1A receptors and previous stressful experience. Eur Neuropsychopharmacol 2014, 24:410-419.
40. Garcia-Arencibia M., Garcia C., Fernandez-Ruiz J. Cannabinoids and Parkinson's disease. CNS Neurol Disord Drug Targets 2009, 8:432-439.
41. Garcia-Oscos F., Pena D., Housini M., et al. Vagal nerve stimulation blocks interleukin 6-dependent synaptic hyperexcitability induced by lipopolysaccharide-induced acute stress in the rodent prefrontal cortex. Brain Behav Immun 2014, 10.1016/j.bbi.2014.07.020.
42. Grassi-Oliveira R., Bauer M.E., Pezzi J.C., Teixeira A.L., Brietzke E. Interleukin-6 and verbal memory in recurrent major depressive disorder. Neuro Endocrinol Lett 2011, 32:540-544.
43. Haji N., Mandolesi G., Gentile A., et al. TNF-alpha-mediated anxiety in a mouse model of multiple sclerosis. Exp Neurol 2012, 237:296-303.
44. Hu S., Sheng W.S., Rock R.B. Immunomodulatory properties of kappa opioids and synthetic cannabinoids in HIV-1 neuropathogenesis. Neuroimmune Pharmacol 2011, 6:528-539.
45. Ickes B.R., Pham T.M., Sanders L.A., Albeck D.S., Mohammed A.H., Granholm A.C. Long-term environmental enrichment leads to regional increases in neurotrophin levels in rat brain. Experimental Neurology 2000, 164:45-52.
46. Izzo A.A., Borrelli F., Capasso R., Di Marzo V., Mechoulam R. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci 2009, 30:515-527.
47. Janse C.J., Ramesar J., Waters A.P. High-efficiency transfection and drug selection of genetically transformed blood stages of the rodent malaria parasite Plasmodium berghei. Nat Protoc 2006, 1:346-356.
48. John C.C., Panoskaltsis-Mortari A., Opoka R.O., Park G.S., Orchard P.J., Jurek A.M., Idro R., Byarugaba J., Boivin M.J. Cerebrospinal fluid cytokine levels and cognitive impairment in cerebral malaria. Am J Trop Med Hyg 2008, 78:198-205.
49. Kaplan B.L. The role of CB1 in immune modulation by cannabinoids. Pharmacol Ther 2013, 137:365-374.
50. 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.
51. 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.
52. Lacerda-Queiroz N., Rodrigues D.H., Vilela M.C., Miranda A.S., Amaral D.C., Camargos E.R., Carvalho L.J., Howe C.L., Teixeira M.M., Teixeira A.L. Inflammatory changes in the central nervous system are associated with behavioral impairment in Plasmodium berghei (strain ANKA)-infected mice. Exp Parasitol 2010, 125:271-278.
53. Lee C., Rodgers R.J. Effects of benzodiazepine receptor antagonist, flumazenil, on antinociceptive and behavioural responses to the elevated plus-maze in mice. Neuropharmacology 1991, 30:1263-1267.
54. Levi-Montalcini R., Skaper S.D., Dal Toso R., Petrelli L., Leon A. Nerve growth factor: from neurotrophin to neurokine. Trends Neurosci 1996, 19:514-520.
55. Liu S., Wang X., Li Y., et al. Necroptosis mediates TNF-induced toxicity of hippocampal neurons. Biomed Res Int 2014, 2014:290182.
56. Magen I., Avraham Y., Ackerman Z., Vorobiev L., Mechoulam R., Berry E.M. Cannabidiol ameliorates cognitive and motor impairments in bile-duct ligated mice via 5-HT1A receptor activation. Br J Pharmacol 2010, 159:950-957.
57. Marchalant Y., Brothers H.M., Norman G.J., Karelina K., DeVries A.C., Wenk G.L. Cannabinoids attenuate the effects of aging upon neuroinflammation and neurogenesis. Neurobiol Dis 2009, 34:300-307.
58. Mecha M., Feliu A., Inigo P.M., Mestre L., Carrillo-Salinas F.J., Guaza C. Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: a role for A2A receptors. Neurobiol Dis 2013, 59:141-150.
59. Mechoulam R., Gaoni Y. Hashish IV. The isolation of cannabinolic, cannabidiolic and cannabigerolic acids. Tetrahedron 1965, 21:1223-1229.
60. Mendonca V.R., Souza L.C., Garcia G.C., et al. DDX39B (BAT1), TNF and IL6 gene polymorphisms and association with clinical outcomes of patients with Plasmodium vivax malaria. Malar J 2014, 13:278.
61. Miranda A.S., Brant F., Rocha N.P., Cisalpino D., Rodrigues D.H., Souza D.G., Machado F.S., Rachid M.A., Teixeira A.L., Campos A.C. Further evidence for an anti-inflammatory role of artesunate in experimental cerebral malaria. Malar J 2013, 12:388.
62. Mishima K., Hayakawa K., Abe K., Ikeda T., Egashira N., Iwasaki K., Fujiwara M. Cannabidiol prevents cerebral infarction via a serotonergic 5-hydroxytryptamine1A receptor-dependent mechanism. Stroke 2005, 36:1077-1082.
63. Molyneux M.E. Impact of malaria on the brain and its prevention. Lancet 2000, 355:671-672.
64. Mooijaart S.P., Sattar N., Trompet S., Lucke J., Stott D.J., Ford I., Jukema J.W., Westendorp R.G., de Craen A.J. Circulating interleukin-6 concentration and cognitive decline in old age: the PROSPER study. J Intern Med 2013, 274:77-85. Group, P.S.
65. Murphy T.M., O'Donovan A., Mullins N., O'Farrelly C., McCann A., Malone K. Anxiety is associated with higher levels of global DNA methylation and altered expression of epigenetic and interleukin-6 genes. Psychiatr Genet 2014, 10.1097/YPG.0000000000000055.
66. Napimoga M.H., Benatti B.B., Lima F.O., Alves P.M., Campos A.C., Pena-Dos-Santos D.R., Severino F.P., Cunha F.Q., Guimaraes F.S. Cannabidiol decreases bone resorption by inhibiting RANK/RANKL expression and pro-inflammatory cytokines during experimental periodontitis in rats. Int Immunopharmacol 2009, 9:216-222.
67. Patki G., Solanki N., Atrooz F., Allam F., Salim S. Depression, anxiety-like behavior and memory impairment are associated with increased oxidative stress and inflammation in a rat model of social stress. Brain Res 2013, 1539:73-86.
68. Pazos M.R., Mohammed N., Lafuente H., Santos M., Martinez-Pinilla E., Moreno E., Valdizan E., Romero J., Pazos A., Franco R., Hillard C.J., Alvarez F.J., Martinez-Orgado J. Mechanisms of cannabidiol neuroprotection in hypoxic-ischemic newborn pigs: role of 5HT1A and CB2 receptors. Neuropharmacology 2013, 71:282-291.
69. Pertwee R.G. Pharmacological actions of cannabinoids. Handb Exp Pharmacol 2005, 1-51.
70. Pino P. From technology to biology: a malaria genetic toolbox for the functional dissection of essential genes. Mol Microbiol 2013, 88:650-654.
71. Reis P.A., Comim C.M., Hermani F., Silva B., Barichello T., Portella A.C., Gomes F.C., Sab I.M., Frutuoso V.S., Oliveira M.F., Bozza P.T., Bozza F.A., Dal-Pizzol F., Zimmerman G.A., Quevedo J., Castro-Faria-Neto H.C. Cognitive dysfunction is sustained after rescue therapy in experimental cerebral malaria, and is reduced by additive antioxidant therapy. PLoS Pathog 2010, 6:e1000963.
72. Rosas-Vidal L.E., Do-Monte F.H., Sotres-Bayon F., Quirk G.J. Hippocampal-prefrontal BDNF and memory for fear extinction. Neuropsychopharmacology 2014, 39:2161-2169.
73. Ruiz-Valdepenas L., Martinez-Orgado J.A., Benito C., Millan A., Tolon R.M., Romero J. Cannabidiol reduces lipopolysaccharide-induced vascular changes and inflammation in the mouse brain: an intravital microscopy study. J Neuroinflammation 2011, 8:5.
74. Sagredo O., Ramos J.A., Decio A., Mechoulam R., Fernandez-Ruiz J. Cannabidiol reduced the striatal atrophy caused 3-nitropropionic acid in vivo by mechanisms independent of the activation of cannabinoid, vanilloid TRPV1 and adenosine A2A receptors. Eur J Neurosci 2007, 26:843-851.
75. Saito V.M., Rezende R.M., Teixeira A.L. Cannabinoid modulation of neuroinflammatory disorders. Curr Neuropharmacol 2012, 10:159-166.
76. Sakata K., Martinowich K., Woo N.H., et al. Role of activity-dependent BDNF expression in hippocampal-prefrontal cortical regulation of behavioral perseverance. Proc Natl Acad Sci USA 2013, 110:15103-15108.
77. Sinha S., Mishra S.K., Sharma S., et al. Polymorphisms of TNF-enhancer and gene for FcgammaRIIa correlate with the severity of falciparum malaria in the ethnically diverse Indian population. Malar J 2008, 7:13.
78. Strehl A., Lenz M., Itsekson-Hayosh Z., et al. Systemic inflammation is associated with a reduction in Synaptopodin expression in the mouse hippocampus. Exp Neurol 2014, 261:230-235.
79. Urquhart A.D. Putative pathophysiological interactions of cytokines and phagocytic cells in severe human falciparum malaria. Clin Infect Dis 1994, 19:117-131.
80. Valvassori S.S., Elias G., de Souza B., Petronilho F., Dal-Pizzol F., Kapczinski F., Trzesniak C., Tumas V., Dursun S., Chagas M.H., Hallak J.E., Zuardi A.W., Quevedo J., Crippa J.A. Effects of cannabidiol on amphetamine-induced oxidative stress generation in an animal model of mania. J Psychopharmacol 2011, 25:274-280.
81. Wenisch C., Linnau K.F., Looaresuwan S., Rumpold H. Plasma levels of the interleukin-6 cytokine family in persons with severe Plasmodium falciparum malaria. J Infect Dis 1999, 179:747-750.
82. Yonelinas A.P. The hippocampus supports high-resolution binding in the service of perception, working memory and long-term memory. Behav Brain Res 2013, 254:34-44.
83. Yuan P., Raz N. Prefrontal cortex and executive functions in healthy adults: a meta-analysis of structural neuroimaging studies. Neurosci Biobehav Rev 2014, 42C:180-192.
84. Zanelati T.V., Biojone C., Moreira F.A., Guimaraes F.S., Joca S.R. Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol 2010, 159:122-128.
85. Zuardi A.W., Cosme R.A., Graeff F.G., Guimaraes F.S. Effects of ipsapirone and cannabidiol on human experimental anxiety. J Psychopharmacol 1993, 7:82-88.