Применение каннабиноидов на примере эпилепсии: медицинские, социальные и юридические аспекты

В обзоре приведены исторические сведения о медицинском использовании каннабиноидов от древности до наших дней. Представлены наиболее часто встречающиеся показания к их применению в неврологии, онкологии и психиатрии для лечения таких социально значимых заболеваний, как эпилепсия, болевые синдромы, спастичность, в том числе при рассеянном склерозе, болезни Паркинсона, депрессии, шизофрении, деменции и др. Отражены данные наиболее масштабных и доказательных исследований применения каннабиноидов для лечения эпилепсии. Представлены основные механизмы действия этих препаратов, сведения об эффективности и безопасности, возможных нежелательных явлениях. Обсуждаются ограничения и юридические аспекты. Как показывают данные систематических обзоров и метаанализов, на сегодняшний день в мире накоплено достаточно положительных результатов исследований, которые свидетельствуют об обоснованности медицинского применения каннабиноидов. Вместе с тем необходимы экспериментальные и клинические работы по дальнейшему изучению механизмов их действия, особенностей фармакокинетики и фармакодинамики, их эффективности и безопасности при многих тяжелых и инвалидизирующих заболеваниях.

каннабис, каннабиноиды, эндогенная каннабиноидная система, каннабиноидные рецепторы

1. Russo EB. History of cannabis and its preparations in saga, science, and sobriquet. Chem Biodivers. 2007;4(8):1614-48. doi: 10.1002/cbdv.200790144

2. Baron EP. Comprehensive review of medicinal marijuana, cannabinoids, and therapeutic implications in medicine and headache: what a long strange trip it's been…. Headache: J Head Face Pain. 2015;55(6):885-916. doi: 10.1111/head.12570

3. Friedman D, Sirven JI. Historical perspective on the medical use of cannabis for epilepsy: Ancient times to the 1980s. Epilepsy Behav. 2017;70(Pt B):298-301. doi: 10.1016/j.yebeh.2016.11.033

4. Touw M. The religious and medicinal uses of Cannabis in China, India and Tibet. J Psychoactive Drugs. 1981;13(1):23-34. doi: 10.1080/02791072.1981.10471447

5. Lozano I. The Therapeutic use of Cannabis sativa (L.) in Arabic medicine. J Cannabis Ther. 2001;1(1):63-70. doi: 10.1300/J175v01n01_05

6. Bonnie RJ, Whitebread CH. The Marijuana Conviction: A history of marijuana prohibition in the United States. Lindesmith Center; 1999.

7. Russo E. Cannabis for migraine treatment: the once and future prescription? An historical and scientific review. Pain. 1998;76(1-2):3-8. doi: 10.1016/S0304-3959(98)00033-5

8. United Nations Office on Drugs and Crime. Single Convention on Narcotic Drugs of 1961 as amended by the 1972 Protocol. New York: United Nations; 2013. Available at: https://www.unodc.org/documents/commissions/CND/Int_Drug_Control_Conventions/Ebook/The_International_Drug_Control_Conventions_E.pdf

9. Pertwee RG. Cannabinoid pharmacology: the first 66 years. Br J Pharmacol. 2006;147 Suppl 1:S163-71. doi: 10.1038/sj.bjp.0706406

10. Rosenberg EC, Tsien RW, Whalley BJ, Devinsky O. Cannabinoids and Epilepsy. Neurotherapeutics. 2015;12(4):747-68. doi: 10.1007/s13311-015-0375-5

11. Adams R, Pease DC, Clark JH. Isolation of Cannabinol, Cannabidiol and Quebrachitol from Red Oil of Minnesota Wild Hemp. J Am Chem Soc. 1940;62(8):2194-6. doi: 10.1021/ja01865a080

12. Mechoulam R, Shvo Y. Hashish I the structure of cannabidiol. Tetrahedron. 1963;19(12):2073-8. doi: 10.1016/00404020(63)85022-X

13. Gaoni Y, Mechoulam R. Isolation, structure, and partial synthesis of an active constituent of hashish. J Am Chem Soc. 1964;86(8):1646-7. doi: 10.1021/ja01062a046

14. Gaoni Y, Mechoulam R. The isolation and structure of delta-1-tetrahydrocannabinol and other neutral cannabinoids from hashish. J Am Chem Soc. 1971;93(1):217-24. doi: 10.1021/ja00730a036

15. Huestis MA, Henningfield JE, Cone EJ. Blood cannabinoids. II. Models for the prediction of time of marijuana exposure from plasma concentrations of Δ9-tetrahydrocannabinol (THC) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH). J Analyt Toxicol. 1992;16(5):283-90. doi: 10.1093/jat/16.5.283

16. Goodwin RS, Gustafson RA, Barnes A, et al. Delta(9)-tetrahydrocannabinol, 11hydroxy-delta(9)-tetrahydrocannabinol and 11nor-9-carboxy-delta(9)-tetrahydrocannabinol in human plasma after controlled oral administration of cannabinoids. Ther Drug Monit. 2006;28(4):545-51. doi: 10.1097/00007691200608000-00010

17. Koppel BS, Brust JCM, Fife T, et al. 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. 2014;82(17):1556-63. doi: 10.1212/WNL.0000000000000363

18. Eisenberg E, Ogintz M, Almog S. The pharmacokinetics, efficacy, safety, and ease of use of a novel portable metered-dose cannabis inhaler in patients with chronic neuropathic pain: a phase 1a study. J Pain Palliative Care Pharmacother. 2014;28(3):216-25. doi: 10.3109/15360288.2014.941130

19. Lu Y, Anderson HD. Cannabinoid signaling in health and disease. Can J Physiol Pharmacol. 2017;95(4):311-27. doi: 10.1139/cjpp-20160346

20. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365(6441):61-5. doi: 10.1038/365061a0

21. Howlett AC, Barth F, Bonner TI, et al. International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors. Pharmacol Rev. 2002;54(2):161-202. doi: 10.1124/pr.54.2.161

22. Quarta C, Bellocchio L, Mancini G, et al. CB1 signaling in forebrain and sympathetic neurons is a key determinant of endocannabinoid actions on energy balance. Cell Metabolism. 2010;11(4):273-85. doi: 10.1016/j.cmet.2010.02.015

23. Marsicano G, Goodenough S, Monory K, et al. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science. 2003;302(5642):84-8. doi: 10.1126/science.1088208

24. Wallace MJ, Blair RE, Falenski KW, et al. The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy. J Pharmacol Exp Ther. 2003;307(1):129-37. doi: 10.1124/jpet.103.051920

25. Gebremedhin D, Lange AR, Campbell WB, et al. Cannabinoid CB1 receptor of cat cerebral arterial muscle functions to inhibit L-type Ca2+ channel current. Am J Physiol. 1999;276(6):H2085-93. doi: 10.1152/ajpheart.1999.276.6.H2085

26. Fimiani C, Mattocks D, Cavani F, et al. Morphine and anandamide stimulate intracellular calcium transients in human arterial endothelial cells: coupling to nitric oxide release. Cell Signal. 1999;11(3):189-93. doi: 10.1016/S0898-6568(98)00060-6

27. Guo S, Liu Y, Ma R, et al. Neuroprotective effect of endogenous cannabinoids on ischemic brain injury induced by the excess microgliamediated inflammation. Am J Transl Res. 2016;8(6):2631-40.

28. Bravo-Ferrer I, Cuartero MI, Zarruk JG, et al. Cannabinoid type-2 receptor drives neurogenesis and improves functional outcome after stroke. Stroke. 2017;48(1):204-12. doi: 10.1161/STROKEAHA.116.014793

29. Ford BM, Tai S, Fantegrossi WE, Prather PL. Synthetic Pot: Not Your Grandfather's Marijuana. Trends Pharmacol Sci. 2017;38(3):257-76. doi: 10.1016/j.tips.2016.12.003

30. Chin JH, Vora N. The global burden of neurologic diseases. Neurology. 2014;83(4):349-51. doi: 10.1212/WNL.0000000000000610

31. Hill AJ, Williams CM, Whalley BJ, Stephens GJ. Phytocannabinoids as novel therapeutic agents in CNS disorders. Pharmacol Ther. 2012;133(1):79-97. doi: 10.1016/j.pharmthera.2011.09.002

32. Jones NA, Hill AJ, Smith I, et al. Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. J Pharmacol Exp Ther. 2010;332(2):569-77. doi: 10.1124/jpet.109.159145

33. Hill TDM, Cascio M-G, Romano B, et al. Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB1 receptor-independent mechanism. Br J Pharmacol. 2013;170(3):679-92. doi: 10.1111/bph.12321

34. Jones NA, Glyn SE, Akiyama S, et al. Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures. Seizure. 2012;21(5):344-52. doi: 10.1016/j.seizure.2012.03.001

35. Jones N, Hill A, Hill T, et al. Assessment of the anticonvulsant effects and tolerability profile of cannabidiol: GW Pharmaceuticals' Preclinical Program (P4.255). Neurology. 2015;84(14 Suppl):P4.255.

36. Dos Santos RG, Hallak JEC, Leite JP, et al. Phytocannabinoids and epilepsy. J Clin Pharm Ther. 2015;40(2):135-43. doi: 10.1111/jcpt.12235

37. Shubina L, Aliev R, Kitchigina V. Endocannabinoid-dependent protection against kainic acid-induced long-term alteration of brain oscillations in guinea pigs. Brain Res. 2017;1661:1-14. doi: 10.1016/j.brainres.2017.02.003

38. Reddy DS, Golub VM. The pharmacological basis of cannabis therapy for epilepsy. J Pharmacol Exp Ther. 2016;357(1):45-55. doi: 10.1124/jpet.115.230151

39. Leo A, Russo E, Elia M. Cannabidiol and epilepsy: Rationale and therapeutic potential. Pharmacol Res. 2016;107:85-92. doi: 10.1016/j.phrs.2016.03.005

40. Keeler MH, Reifler CB. Grand mal convulsions subsequent to marijuana use. Dis Nerv Syst. 1967;28(7, Pt. 1):474-5.

41. Consroe PF, Wood GC, Buchsbaum H. Anticonvulsant nature of marihuana smoking. JAMA. 1975;234(3):306-7. doi: 10.1001/jama.1975.03260160054015

42. Feeney DM. The marijuana window: a theory of cannabis use. Behav Biol. 1976;18(4):455-71. doi: 10.1016/S00916773(76)92488-3

43. Gordon E, Devinsky O. Alcohol and marijuana: effects on epilepsy and use by patients with epilepsy. Epilepsia. 2001;42(10):1266-72. doi: 10.1046/j.1528-1157.2001.19301.x

44. Hamerle M, Ghaeni L, Kowski A, et al. Cannabis and other illicit drug use in epilepsy patients. Eur J Neurol. 2014;21(1):167-70. doi: 10.1111/ene.12081

45. Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev. 2012;(6):CD009270. doi: 10.1002/14651858.CD009270.pub2

46. Cilio MR, Thiele EA, Devinsky O. The case for assessing cannabidiol in epilepsy. Epilepsia. 2014;55(6):787-90. doi: 10.1111/epi.12635

47. Maa E, Figi P. The case for medical marijuana in epilepsy. Epilepsia. 2014;55(6):783-6. doi: 10.1111/epi.12610

48. Saade D, Joshi C. Pure cannabidiol in the treatment of malignant migrating partial seizures in infancy: a case report. Pediatr Neurol. 2015;52(5):544-7. doi: 10.1016/j.pediatrneurol.2015.02.008

49. Press CA, Knupp KG, Chapman KE. Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy. Epilepsy Behav. 2015;45:49-52. doi: 10.1016/j.yebeh.2015.02.043

50. Porter BE, Jacobson C. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy Behav. 2013;29(3):574-7. doi: 10.1016/j.yebeh.2013.08.037

51. Campbell CT, Phillips MS, Manasco K. Cannabinoids in pediatrics. J Pediatr Pharmacol Ther. 2017;22(3):176-85. doi: 10.5863/1551-6776-22.3.176

52. Mathern GW, Beninsig L, Nehlig A. 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. 2015;56(1):1-6. doi: 10.1111/epi.12843

53. Devinsky O, Cilio MR, Cross H, et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014;55(6):791-802. doi: 10.1111/epi.12631

54. Devinsky O, Patel A, Cross J, et al. Effect of cannabidiol on drop seizures in the LennoxGastaut syndrome. N Engl J Med. 2018;378:1888-97. doi: 10.1056/NEJMoa1714631

55. Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the dravet syndrome. N Engl J Med. 2017;376(21):2011-20. doi: 10.1056/NEJMoa1611618

56. Devinsky O, Patel AD, Thiele EA, et al. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology. 2018;90(14):e1204-e1211. doi: 10.1212/WNL.0000000000005254

57. Devinsky O, Nabbout R, Miller I, et al. Long-term cannabidiol treatment in patients with Dravet syndrome: An open-label extension trial. Epilepsia. 2019;60(2):294-302. doi: 10.1111/epi.14628

58. Szaflarski JP, Bebin EM, Comi AM, et al. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results. Epilepsia. 2018;59(8):1540-8. doi: 10.1111/epi.14477

59. Thiele E, Marsh E, MazurkiewiczBeldzinska M, et al. Cannabidiol in patients with Lennox-Gastaut syndrome: Interim analysis of an open-label extension study. Epilepsia. 2019;60(3):419-28. doi: 10.1111/epi.14670

60. Silvestro S, Mammana S, Cavalli E, et al. Use of cannabidiol in the treatment of epilepsy: efficacy and security in clinical trials. Molecules. 2019;24(8):1459. doi: 10.3390/molecules24081459

61. Sekar K, Pack A. Epidiolex as adjunct therapy for treatment of refractory epilepsy: a comprehensive review with a focus on adverse effects. F1000Research. 2019;8(F1000 Faculty Rev):234. doi: 10.12688/f1000research.16515.1

62. Ali S, Scheffer IE, Sadleir LG. Efficacy of cannabinoids in paediatric epilepsy. Dev Med Child Neurol. 2019;61(1):13-8. doi: 10.1111/dmcn.14087

63. Friedman D, Devinsky O. Cannabinoids in the treatment of epilepsy. Longo DL, ed. N Engl J Med. 2015;373(11):1048-58. doi: 10.1056/NEJMra1407304