The pharmacological basis of cannabis therapy for epilepsy

Journal of Pharmacology and Experimental Therapeutics

Volumn 357, Issue 1, 2016, Pages 45-55

  Reddy, Doodipala Samba ^a   Golub, Victoria M ^a  

^a TEXAS A M COLLEGE OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTICONVULSIVE AGENT; CANNABIDIOL; CANNABIS; MEDICAL CANNABIS;

ANIMAL; EPILEPSY; HUMAN;

ANIMALS; ANTICONVULSANTS; CANNABIDIOL; CANNABIS; EPILEPSY; HUMANS; MEDICAL MARIJUANA;

EID: 84962511135     PISSN: 00223565     EISSN: 15210103     Source Type: Journal    
DOI: 10.1124/jpet.115.230151     Document Type: Review

References (118)

1. Alger BE (2014) Seizing an opportunity for the endocannabinoid system. Epilepsy Curr 14:272-276.
2. Ames FR and Cridland S (1986) Anticonvulsant effect of cannabidiol. S Afr Med J 69:14-18.
3. Ashton JC and Glass M (2007) The cannabinoid CB2 receptor as a target for inflammation-dependent neurodegeneration. Curr Neuropharmacol 5:73-80.
4. Bahremand A, Shafaroodi H, Ghasemi M, Nasrabady SE, Gholizadeh S, and Dehpour AR (2008) The cannabinoid anticonvulsant effect on pentylenetetrazole-induced seizure is potentiated by ultra-low dose naltrexone in mice. Epilepsy Res 81:44-51.
5. Baron EP (2015) Comprehensive review of medicinal marijuana, cannabinoids, and therapeutic implications in medicine and headache: What a long strange trip it's been. Headache 55:885-916.
6. Barrese V, Miceli F, Soldovieri MV, Ambrosino P, Iannotti FA, Cilio MR, and Taglialatela M (2010) Neuronal potassium channel openers in the management of epilepsy: role and potential of retigabine. Clin Pharmacol 2:225-236.
7. Basu S, Ray A, and Dittel BN (2011) Cannabinoid receptor 2 is critical for the homing and retention of marginal zone B lineage cells and for efficient T-independent immune responses. J Immunol 187:5720-5732.
8. Blair RE, Deshpande LS, and De Lorenzo RJ (2015) Cannabinoids: is there a potential treatment role in epilepsy? Expert Opin Pharmacother 16:1911-1914.
9. Bosier B, Sarre S, Smolders I, Michotte Y, Hermans E, and Lambert DM (2010) Revisiting the complex influences of cannabinoids on motor functions unravels pharmacodynamic differences between cannabinoid agonists. Neuropharmacology 59:503-510.
10. Brodie JS, Di Marzo V, and Guy GW (2015) Polypharmacology shakes hands with complex aetiopathology. Trends Pharmacol Sci 36:802-821.
11. Cabral GA, Rogers TJ, and Lichtman AH (2015) Turning over a new leaf: Cannabinoid and endocannabinoid modulation of immune function. J Neuroimmune Pharmacol 10:193-203.
12. Campos AC, Moreira FA, Gomes FV, Del Bel EA, and Guimarães FS (2012) Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos Trans R Soc Lond B Biol Sci 367:3364-3378.
13. Capasso R, Borrelli F, Aviello G, Romano B, Scalisi C, Capasso F, and Izzo AA (2008) Cannabidiol, extracted from Cannabis sativa, selectively inhibits inflammatory hypermotility in mice. Br J Pharmacol 154:1001-1008.
14. Cascio MG and Pertwee RG (2014) Known pharmacological actions of nine nonpsychotropic phytocannabinoids, in: Handbook of Cannabis (Pertwee RG ed) p. 137, Oxford University Press, Oxford, UK.
15. Ceulemans B, Boel M, Leyssens K, Van Rossem C, Neels P, Jorens PG, and Lagae L (2012) Successful use of fenfluramine as an add-on treatment for Dravet syndrome. Epilepsia 53:1131-1139.
16. Cheng Y and Hitchcock SA (2007) Targeting cannabinoid agonists for inflammatory and neuropathic pain. Expert Opin Investig Drugs 16:951-965.
17. Chiu P, Olsen DM, Borys HK, Karler R, and Turkanis SA (1979) The influence of cannabidiol and delta 9-tetrahydrocannabinol on cobalt epilepsy in rats. Epilepsia 20:365-375.
18. Consroe P, Benedito MA, Leite JR, Carlini EA, Mechoulam R, and Mechoulam R (1982) Effects of cannabidiol on behavioral seizures caused by convulsant drugs or current in mice. Eur J Pharmacol 83:293-298.
19. Consroe PF, Wood GC, and Buchsbaum H (1975) Anticonvulsant nature of marihuana smoking. JAMA 234:306-307.
20. Cunha JM, Carlini EA, Pereira AE, Ramos OL, Pimentel C, Gagliardi R, Sanvito WL, Lander N, and Mechoulam R (1980) Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology 21:175-185.
21. Davis JP and Ramsey H (1949) Anti-epileptic action of marijuana-active substances. Fed Amer Soc Exper Bio 8:284.
22. Deshpande LS, Sombati S, Blair RE, Carter DS, Martin BR, and De Lorenzo RJ (2007) Cannabinoid CB1 receptor antagonists cause status epilepticus-like activity in the hippocampal neuronal culture model of acquired epilepsy. Neurosci Lett 411:11-16.
23. Detyniecki K and Hirsch L (2015) Marijuana use in epilepsy: The myth and the reality. Curr Neurol Neurosci Rep 15:65-70.
24. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, and Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946-1949.
25. Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, Katz R, Di Marzo V, Jutras-Aswad D, and Notcutt WG, et al. (2014a) Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 55:791-802.
26. Devinsky O, Sullivan J, Friedman D, Thiele E, Marsh E, Laux L, Hedlund J, Tilton N, Bluvstein J, and Cilio M (2014b) Efficacy and safety of Epidiolex (cannabidiol) in children and young adults with treatment-resistant epilepsy: Initial data from an expanded access program, in Proceedings of the American Epilepsy Society Annual Meeting; 2014 Dec. 5-9; Seattle, WA. American Epilepsy Society, Chicago, IL.
27. Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, Kathuria S, and Piomelli D (2002a) Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci USA 99:10819-10824.
28. Dinh TP, Freund TF, and Piomelli D (2002b) A role for monoglyceride lipase in 2-arachidonoylglycerol inactivation. Chem Phys Lipids 121:149-158.
29. Duncan JS, Sander JW, Sisodiya SM, and Walker MC (2006) Adult epilepsy. Lancet 367:1087-1100.
30. Elphick MR and Egertová M (2001) The neurobiology and evolution of cannabinoid signalling. Philos Trans R Soc Lond B Biol Sci 356:381-408.
31. El Sohly M and Gul W (2014) Constituents of cannabis sativa, in: Handbook of Cannabis (Pertwee RG ed) pp. 3-22, Oxford University Press, Oxford, UK.
32. Eisenstein M (2015) Medical marijuana: Showdown at the cannabis corral. Nature 525:S15-S17.
33. Falenski KW, Carter DS, Harrison AJ, Martin BR, Blair RE, and De Lorenzo RJ (2009) Temporal characterization of changes in hippocampal cannabinoid CB (1) receptor expression following pilocarpine-induced status epilepticus. Brain Res 1262:64-72.
34. French L, Gray C, Leonard G, Perron M, Pike GB, Richer L, Séguin JR, Veillette S, Evans CJ, and Artiges E, et al. (2015) Early cannabis use, polygenic risk score for schizophrenia and brain maturation in adolescence. JAMA Psychiatry 72:1002-1011 Epub ahead of print.
35. Friedman D, Cilio MR, Tilton N, Sullivan J, Hedlund J, Rosenburg E, Bluvstein J, and Devinsky O (2014) The effect of Epidiolex (cannabidiol) on serum levels of concomitant anti-epileptic drugs in children and young adults with treatmentresistant epilepsy in an expanded access program, in Proceedings of the American Epilepsy Society Annual Meeting; 2014 Dec. 5-9; Seattle, WA. Abst. 2.309, American Epilepsy Society, Chicago, IL.
36. Friedman D and Devinsky O (2015) Cannabinoids in the treatment of epilepsy. N Engl J Med 373:1048-1058.
37. Galiègue S, Mary S, Marchand J, Dussossoy D, Carrière D, Carayon P, Bouaboula M, Shire D, Le Fur G, and Casellas P (1995) Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 232:54-61.
38. Gardner EL and Vorel SR (1998) Cannabinoid transmission and reward-related events. Neurobiol Dis 5(6 Pt B):502-533.
39. Gedde MM and Maa E (2013) Whole cannabis extract of high concentration cannabidiol may calm seizures in highly refractory pediatric epilepsies. in Proceedings of the American Epilepsy Society Annual Meeting; 2014 Dec. 5-9; Seattle, WA. Abst. 3.330, American Epilepsy Society, Chicago, IL.
40. Geffrey AL, Pollack SF, Bruno PL, and Thiele EA (2015) Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia 56:1246-1251.
41. Gérard CM, Mollereau C, Vassart G, and Parmentier M (1991) Molecular cloning of a human cannabinoid receptor which is also expressed in testis. Biochem J 279:129-134.
42. Gloss D and Vickery B (2014) Cannabinoids for epilepsy. Cochrane Database Syst Rev 3: CD009270 DOI: 10.1002/14651858. CD009270.pub3.
43. Goldman D (2015) America's cannabis experiment. JAMA Psychiatry 72:969-970 Epub ahead of print.
44. Goodman J and Packard MG (2015) The influence of cannabinoids on learning and memory processes of the dorsal striatum. Neurobiol Learn Mem 125:1-14.
45. Gowers WR (1881) Epilepsy and Other Chronic Convulsive Diseases: Their Causes, Symptoms and Treatment, J&A Churchill, New Burlington Street, London. [Web].
46. GW Pharmaceuticals plc (Press Release, April, 2015). GW Pharmaceuticals Announces New Physician Reports of Epidiolex® Treatment Effect in Children and Young Adults with Treatment-Resistant Epilepsy.. GW Pharmaceuticals plc, Cambridge, UK.
47. Hampson AJ, Grimaldi M, Axelrod J, and Wink D (1998) Cannabidiol and (-) D9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA 95:8268-8273.
48. Hansen B, Szaflarski M, Bebin M, and Szaflarski J (2015) Socioeconomic characteristics of patients in the Alabama study of cannabidiol (CBD) use to treat epilepsy, in: Proceedings of the American Epilepsy Society Annual Meeting; 2015 Dec. 4-8; Philadelphia, PA. Abst. 2.375, American Epilepsy Society, Chicago, IL.
49. Häring M, Kaiser N, Monory K, and Lutz B (2011) Circuit specific functions of cannabinoid CB1 receptor in the balance of investigatory drive and exploration. PLoS One 6:e26617.
50. Hesdorffer DC, Beck V, Begley CE, Bishop ML, Cushner-Weinstein S, Holmes GL, Shafer PO, Sirven JI, and Austin JK (2013) Research implications of the institute of medicine report, epilepsy across the spectrum: Promoting health and understanding. Epilepsia 54:207-216.
51. Hill AJ, Mercier MS, Hill TDM, Glyn SE, Jones NA, Yamasaki Y, Futamura T, Duncan M, Stott CG, and Stephens GJ, et al. (2012) Cannabidivarin is anticonvulsant in mouse and rat. Br J Pharmacol 167:1629-1642.
52. Hill MN, McLaughlin RJ, Bingham B, Shrestha L, Lee TTY, Gray JM, Hillard CJ, Gorzalka BB, and Viau V (2010) Endogenous cannabinoid signaling is essential for stress adaptation. Proc Natl Acad Sci USA 107:9406-9411.
53. Hill TDM, Cascio MG, Romano B, Duncan M, Pertwee RG, Williams CM, Whalley BJ, and Hill AJ (2013) Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB1 receptor-independent mechanism. Br J Pharmacol 170:679-692.
54. Hofmann ME and Frazier CJ (2013) Marijuana, endocannabinoids, and epilepsy: potential and challenges for improved therapeutic intervention. Exp Neurol 244:43-50.
55. Hoheisel U, Taguchi T, Treede RD, and Mense S (2011) Nociceptive input from the rat thoracolumbar fascia to lumbar dorsal horn neurones. Eur J Pain 15:810-815.
56. Iannotti FA, Hill CL, Leo A, Alhusaini A, Soubrane C, Mazzarella E, Russo E, Whalley BJ, Di Marzo V, and Stephens GJ (2014) Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability. ACS Chem Neurosci 5:1131-1141.
57. Ibeas Bih C, Chen T, Nunn AVW, Bazelot M, Dallas M, and Whalley BJ (2015) Molecular targets of cannabidiol in neurological disorders. Neurotherapeutics 12:699-730.
58. Jones NA, Glyn SE, Akiyama S, Hill TD, Hill AJ, Weston SE, Burnett MD, Yamasaki Y, Stephens GJ, and Whalley BJ, et al. (2012) Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures. Seizure 21:344-352.
59. Jones NA, Hill AJ, Smith I, Bevan SA, Williams CM, Whalley BJ, and Stephens GJ (2010) Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. J Pharmacol Exp Ther 332:569-577.
60. Jones N, Hill T, Stott C, and Wright S (2015) Assessment of the anticonvulsant effects and tolerability of GW Pharmaceuticals' cannabidiol in the anticonvulsant screening program, in: Proceedings of the American Epilepsy Society Annual Meeting; 2015 Dec. 4-8; Philadelphia, PA. Abst. 3.034., American Epilepsy Society, Chicago, IL.
61. Karler R, Calder LD, Sangdee P, and Turkanis SA (1984) Interaction between delta-9-tetrahydrocannabinol and kindling by electrical and chemical stimuli in mice. Neuropharmacology 23:1315-1320.
62. Katona I, Rancz EA, Acsady L, Ledent C, Mackie K, Hajos N, and Freund TF (2001) Distribution of CB1 cannabinoid receptors in the amygdala and their role in the control of GABAergic transmission. J Neurosci 21:9506-9518.
63. Koppel BS, Brust JCM, Fife T, Bronstein J, Youssof S, Gronseth G, and Gloss D (2014) Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 82:1556-1563.
64. Kros L, Eelkman Rooda OH, De Zeeuw CI, Hoebeek FE, and Hoebeek FE (2015) Controlling cerebellar output to treat refractory epilepsy. Trends Neurosci 38:787-799.
65. Lee J, Di Marzo V, and Brotchie JM (2006) A role for vanilloid receptor 1 (TRPV1) and endocannabinnoid signalling in the regulation of spontaneous and L-DOPA induced locomotion in normal and reserpine-treated rats. Neuropharmacology 51:557-565.
66. Li K, Feng JY, Li YY, Yuece B, Lin XH, Yu LY, Li YN, Feng YJ, and Storr M (2013) Anti-inflammatory role of cannabidiol and O-1602 in cerulein-induced acute pancreatitis in mice. Pancreas 42:123-129.
67. Liou GI, Auchampach JA, Hillard CJ, Zhu G, Yousufzai B, Mian S, Khan S, and Khalifa Y (2008) Mediation of cannabidiol anti-inflammation in the retina by equilibrative nucleoside transporter and A2A adenosine receptor. Invest Ophthalmol Vis Sci 49:5526-5531.
68. Ludányi A, Eross L, Czirják S, Vajda J, Halász P, Watanabe M, Palkovits M, Maglóczky Z, Freund TF, and Katona I (2008) Downregulation of the CB1 cannabinoid receptor and related molecular elements of the endocannabinoid system in epileptic human hippocampus. J Neurosci 28:2976-2990.
69. Luszczki JJ, Andres-Mach M, Barcicka-Klosowska B, Florek-Luszczki M, Haratym-Maj A, and Czuczwar SJ (2011a) Effects of WIN 55, 212-2 mesylate (a synthetic cannabinoid) on the protective action of clonazepam, ethosuximide, phenobarbital and valproate against pentylenetetrazole-induced clonic seizures in mice. Prog Neuropsychopharmacol Biol Psychiatry 35:1870-1876.
70. Luszczki JJ, Czuczwar P, Cioczek-Czuczwar A, Dudra-Jastrzebska M, Andres-Mach M, and Czuczwar SJ (2010) Effect of arachidonyl-29-chloroethylamide, a selective cannabinoid CB1 receptor agonist, on the protective action of the various antiepileptic drugs in the mouse maximal electroshock-induced seizure model. Prog Neuropsychopharmacol Biol Psychiatry 34:18-25.
71. Luszczki JJ, Misiuta-Krzesinska M, Florek M, Tutka P, and Czuczwar SJ (2011b) Synthetic cannabinoid WIN 55, 212-2 mesylate enhances the protective action of four classical antiepileptic drugs against maximal electroshock-induced seizures in mice. Pharmacol Biochem Behav 98:261-267.
72. Maa E and Figi P (2014) The case for medical marijuana in epilepsy. Epilepsia 55:783-786.
73. Mailleux P and Vanderhaeghen JJ (1992) Distribution of neuronal cannabinoid receptor in the adult rat brain: a comparative receptor binding radioautography and in situ hybridization histochemistry. Neuroscience 48:655-668.
74. Malfait AM, Gallily R, Sumariwalla PF, Malik AS, Andreakos E, Mechoulam R, and Feldmann M (2000) The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci USA 97:9561-9566.
75. Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, Azad SC, Cascio MG, Gutiérrez SO, and Van Der Stelt M, et al. (2003) CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302:84-88.
76. Martin AR, Consroe P, Kane VV, Shah V, Singh V, Lander N, Mechoulam R, and Srebnik M (1987) Structure-anticonvulsant activity relationships of cannabidiol analogs. NIDA Res Monogr 79:48-58.
77. Martin P and Consroe P (1976) Cannabinoid induced behavioral convulsions in rabbits. Science 194:965-967.
78. Mathern GW, Beninsig L, and Nehlig A (2015) Fewer specialists support using medical marijuana and CBD in treating epilepsy patients compared with other medical professionals and patients: result of Epilepsia's survey. Epilepsia 56:1-6.
79. Matias I, Pochard P, Orlando P, Salzet M, Pestel J, and Di Marzo V (2002) Presence and regulation of the endocannabinoid system in human dendritic cells. Eur J Biochem 269:3771-3778.
80. McAllister SD, Murase R, Christian RT, Lau D, Zielinski AJ, Allison J, Almanza C, Pakdel A, Lee J, and Limbad C, et al. (2011) Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis. Breast Cancer Res Treat 129:37-47.
81. Mechoulam R (1986) The pharmacohistory of Cannabis sativa, in Cannabinoids as Therapeutic Agents (Meechoulam R ed) pp 1-19, CRC Press, Boca Raton, FL.
82. Mechoulam R and Carlini EA (1978) Toward drugs derived from cannabis. Naturwissenschaften 65:174-179.
83. Meldrum BS, Fariello RG, Puil EA, Derouaux M, and Naquet R (1974) D9-tetrahydrocannabinol and epilepsy in the photosensitive baboon, Papio papio. Epilepsia 15:255-264.
84. Munro S, Thomas KL, and Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61-65.
85. Muramoto K, Ono T, Nishijo H, and Fukuda M (1993) Rat amygdaloid neuron responses during auditory discrimination. Neuroscience 52:621-636.
86. Naderi N, Aziz Ahari F, Shafaghi B, Najarkolaei AH, and Motamedi F (2008) Evaluation of interactions between cannabinoid compounds and diazepam in electroshock-induced seizure model in mice. J Neural Transm (Vienna) 115:1501-1511.
87. Naderi N, Shafieirad E, Lakpoor D, Rahimi A, and Mousavi Z (2015) Interaction between cannabinoid compounds and capsazepine in protection against acute pentylenetetrazole-induced seizure in mice. Iran J Pharm Res 14(Suppl):115-120.
88. Nomura DK, Morrison BE, Blankman JL, Long JZ, Kinsey SG, Marcondes MCG, Ward AM, Hahn YK, Lichtman AH, and Conti B, et al. (2011) Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science 334:809-813.
89. Notcutt WG (2015) Clinical use of cannabinoids for symptom control in multiple sclerosis. Neurotherapeutics 12:769-777.
90. Oldham M, Sullivan J, Singhal N, Tilton N, and Cilio M (2015) Long-term efficacy and tolerability of add-on cannabidiol for drug-resistant pediatric epilepsies, in: Proceedings of the American Epilepsy Society Annual Meeting; 2015 Dec. 4-8; Philadelphia, PA. Abst. 2.296, American Epilepsy Society, Chicago, IL.
91. Pagliaccio D, Barch DM, Bogdan R, Wood PK, Lynskey MT, Heath AC, and Agrawal A (2015) Shared predisposition in the association between cannabis use and subcortical brain structure. JAMA Psychiatry 72:994-1001 Epub ahead of print.
92. Patel R, Barbosa-Nunez C, and Cummins T (2014) Epilepsy-associated mutant voltage-gated sodium channels alter resurgent current generation that could be preferentially targeted with cannabidiol, in Proceedings of the American Epilepsy Society Annual Meeting; 2014, Dec. 5-9; Seattle, WA. Abst. 1.294, American Epilepsy Society, Chicago, IL.
93. Pertwee RG (2006) The pharmacology of cannabinoid receptors and their ligands: an overview. Int J Obes 30(Suppl 1):S13-S18.
94. Pertwee RG (2008) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol 153:199-215.
95. Pertwee RG (2012) Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philos Trans R Soc Lond B Biol Sci 367:3353-3363.
96. Pertwee RG and Cascio MG (2014) Known pharmacological actions of delta-9-tetrahydrocannabinol and of four other chemical constituents of cannabis that activate cannabinoid receptors, in: Handbook of Cannabis (Pertwee RG ed) p. 115, Oxford University Press, Oxford, UK.
97. Perucca P and Gilliam FG (2012) Adverse effects of antiepileptic drugs. Lancet Neurol 11:792-802.
98. Porter BE and Jacobson C (2013) Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy Behav 29:574-577.
99. Press CA, Knupp KG, and Chapman KE (2015) Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy. Epilepsy Behav 45:49-52.
100. Reddy DS (2014) Clinical pharmacology of current antiepileptic drugs. Internat. J. Pharma. Sci. Nano. 7:2305-2319.
101. Rektor I, Schachter SC, Arya R, Arzy S, Braakman H, Brodie MJ, Brugger P, Chang BS, Guekht A, and Hermann B, et al. (2015) Third international congress on epilepsy, brain, and mind: Part 2. Epilepsy Behav 50:138-159.
102. Romigi A, Bari M, Placidi F, Marciani MG, Malaponti M, Torelli F, Izzi F, Prosperetti C, Zannino S, and Corte F, et al. (2010) Cerebrospinal fluid levels of the endocannabinoid anandamide are reduced in patients with untreated newly diagnosed temporal lobe epilepsy. Epilepsia 51:768-772.
103. Russo EB, Burnett A, Hall B, and Parker KK (2005) Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res 30:1037-1043.
104. Dos Santos RG, Hallak JEC, Leite JP, Zuardi AW, and Crippa JAS (2015) Phytocannabinoids and epilepsy. J Clin Pharm Ther 40:135-143.
105. Scutt A and Williamson EM (2007) Cannabinoids stimulate fibroblastic colony formation by bone marrow cells indirectly via CB2 receptors. Calcif Tissue Int 80:50-59.
106. Smith MD, Wilcox KS, and White S (2015) Analysis of cannabidiol interactions with antiseizure drugs, in: Proceedings of the American Epilepsy Society Annual Meeting; 2015 Dec. 4-8; Philadelphia, PA. Abst. 1.215, American Epilepsy Society, Chicago, IL.
107. Szabo B, Müller T, and Koch H (1999) Effects of cannabinoids on dopamine release in the corpus striatum and the nucleus accumbens in vitro. J Neurochem 73:1084-1089.
108. Tanda G, Pontieri FE, and Di Chiara G (1997) Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism. Science 276:2048-2050.
109. Theodore WH, Hasler G, Giovacchini G, Kelley K, Reeves-Tyer P, Herscovitch P, and Drevets W (2007) Reduced hippocampal 5HT1A PET receptor binding and depression in temporal lobe epilepsy. Epilepsia 48:1526-1530.
110. Tolón RM, Núñez E, Pazos MR, Benito C, Castillo AI, Martínez-Orgado JA, and Romero J (2009) The activation of cannabinoid CB2 receptors stimulates in situ and in vitro beta-amyloid removal by human macrophages. Brain Res 1283:148-154.
111. Trembly B and Sherman M (1990) Double-blind clinical study of cannabidiol as a secondary anticonvulsant, presented at: Marijuana'90 International Conference on Cannabis and Cannabinoids; 1990 July 8-11, Kolymbari, Crete. International Association for Cannabinoid Medicines.
112. Tsou K, Brown S, Sañudo-Peña MC, Mackie K, and Walker JM (1998) Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience 83:393-411.
113. Veeraraghavan P and Nistri A (2015) Modulatory effects by CB1 receptors on rat spinal locomotor networks after sustained application of agonists or antagonists. Neuroscience 303:16-33.
114. Vollner L, Bieniek D, and Korte F (1969) [Hashish. XX. Cannabidivarin, a new hashish constituent]. Tetrahedron Lett 3:145-147.
115. Wallace MJ, Blair RE, Falenski KW, Martin BR, and De Lorenzo RJ (2003) The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy. J Pharmacol Exp Ther 307:129-137.
116. Wallace MJ, Martin BR, and De Lorenzo RJ (2002) Evidence for a physiological role of endocannabinoids in the modulation of seizure threshold and severity. Eur J Pharmacol 452:295-301.
117. Wallace MJ, Wiley JL, Martin BR, and De Lorenzo RJ (2001) Assessment of the role of CB1 receptors in cannabinoid anticonvulsant effects. Eur J Pharmacol 428:51-57.
118. Wissel J, Haydn T, Müller J, Brenneis C, Berger T, Poewe W, and Schelosky LD (2006) Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain: a double-blind placebo-controlled cross-over trial. J Neurol 253:1337-1341.