Vol 69, No 6 (2018)
Review paper
Published online: 2018-12-20

open access

Page views 18591
Article views/downloads 14644
Get Citation

Connect on Social Media

Connect on Social Media

The effects of cannabinoids on the endocrine system

Magdalena Borowska1, Agata Czarnywojtek12, Nadia Sawicka-Gutaj2, Kosma Woliński2, Maria Teresa Płazińska3, Przemysław Mikołajczak1, Marek Ruchała2
Pubmed: 30618031
Endokrynol Pol 2018;69(6):705-719.

Abstract

Cannabinoids are the derivatives of the cannabis plant, the most potent bioactive component of which is tetrahydrocannabinol (THC). The most commonly used drugs containing cannabinoids are marijuana, hashish, and hashish oil. These compounds exert their effects via interaction with the cannabinoid receptors CB1 and CB2. Type 1 receptors (CB1) are localised mostly in the central nervous system and in the adipose tissue and many visceral organs, including most endocrine organs. Type 2 cannabinoid receptors (CB2) are positioned in the peripheral nervous system (peripheral nerve endings) and on the surface of the immune system cells. Recently, more and more attention has been paid to the role that endogenous ligands play for these receptors, as well as to the role of the receptors themselves. So far, endogenous cannabinoids have been confirmed to participate in the regulation of food intake and energy homeostasis of the body, and
have a significant impact on the endocrine system, including the activity of the pituitary gland, adrenal cortex, thyroid gland, pancreas, and gonads. Interrelations between the endocannabinoid system and the activity of the endocrine system may be a therapeutic target for a number of drugs that have been proved effective in the treatment of infertility, obesity, diabetes, and even prevention of diseases associated with the cardiovascular system.

Article available in PDF format

View PDF Download PDF file

References

  1. Komorowski J, Stępień H. Rola układu endokannabinoidowego w regulacji czynności dokrewnej i kontroli równowagi energetycznej człowieka. Postępy Hig Med Dosw. 2007; 61: 99–105.
  2. Besch NF, Smith CG, Besch PK, et al. The effect of marihuana (delta-9-tetrahydrocannabinol) on the secretion of luteinizing hormone in the ovariectomized rhesus monkey. Am J Obstet Gynecol. 1977; 128(6): 635–642.
  3. Cota D, Marsicano G, Lutz B, et al. Endogenous cannabinoid system as a modulator of food intake. Int J Obes Relat Metab Disord. 2003; 27(3): 289–301.
  4. Cota D, Marsicano G, Tschöp M, et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest. 2003; 112(3): 423–431.
  5. Harrold JA, Williams G. The cannabinoid system: a role in both the homeostatic and hedonic control of eating? Br J Nutr. 2003; 90(4): 729–734.
  6. Pagotto U, Marsicano G, Cota D, et al. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev. 2006; 27(1): 73–100.
  7. Gray C. Legalize use of marijuana for medical purposes, MDs and patients plead. CMAJ. 1998; 158(3): 373–375.
  8. Kogan NM, Mechoulam R. The chemistry of endocannabinoids. J Endocrinol Invest. 2006; 29(Suppl 3): 3–14.
  9. Matias I, Di Marzo V. Endocannabinoid synthesis and degradation, and their regulation in the framework of energy balance. J Endocrinol Invest. 2006; 29(3 Suppl): 15–26.
  10. Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992; 258(5090): 1946–1949.
  11. Mechoulam R, Ben-Shabat S, Hanus L, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995; 50(1): 83–90.
  12. Sugiura T, Kondo S, Sukagawa A, et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun. 1995; 215(1): 89–97.
  13. Szukalski B. Perspektywy leczniczych zastosowań kannabinoidów. Farm Pol. 2003; 19: 863–874.
  14. Ameri A. The effects of cannabinoids on the brain. Prog Neurobiol. 1999; 58(4): 315–348.
  15. Porter A, Felder C. The endocannabinoid nervous system. Pharmacology & Therapeutics. 2001; 90(1): 45–60.
  16. van der Stelt M, Di Marzo V. The endocannabinoid system in the basal ganglia and in the mesolimbic reward system: implications for neurological and psychiatric disorders. Eur J Pharmacol. 2003; 480(1–3): 133–150.
  17. Huang SM, Bisogno T, Trevisani M, et al. An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proc Natl Acad Sci U S A. 2002; 99(12): 8400–8405.
  18. Rodríguez de Fonseca F, Navarro M, Gómez R, et al. An anorexic lipid mediator regulated by feeding. Nature. 2001; 414(6860): 209–212.
  19. Sagar DR, Smith PA, Millns PJ, et al. TRPV1 and CB(1) receptor-mediated effects of the endovanilloid/endocannabinoid N-arachidonoyl-dopamine on primary afferent fibre and spinal cord neuronal responses in the rat. Eur J Neurosci. 2004; 20(1): 175–184.
  20. Cota D, Sandoval DA, Olivieri M, et al. Food intake-independent effects of CB1 antagonism on glucose and lipid metabolism. Obesity. 2009; 17(8): 1641–1645.
  21. Horvath TL. Endocannabinoids and the regulation of body fat: the smoke is clearing. J Clin Invest. 2003; 112(3): 323–326.
  22. Nowak P, Brus R. Układ endokanabinowy – przyszłość nowoczesnej farmakoterapii wybranych schorzeń endokrynologicznych u dzieci. In: Otto-Buczkowska E. ed. Endokrynologia wieku rozwojowego — co nowego? Cornetis, Wrocław 2008: 286–293.
  23. Pertwee RG, Howlett AC, Abood ME, et al. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB₁ and CB₂. Pharmacol Rev. 2010; 62(4): 588–631.
  24. Berdyshev EV. Cannabinoid receptors and the regulation of immune response. Chem Phys Lipids. 2000; 108(1–2): 169–190.
  25. Maccarrone M, Falciglia K, Di Rienzo M, et al. Endocannabinoids, hormone-cytokine networks and human fertility. Prostaglandins Leukot Essent Fatty Acids. 2002; 66(2-3): 309–317.
  26. Mackie K, Stella N. Cannabinoid receptors and endocannabinoids: evidence for new players. AAPS J. 2006; 8(2): E298–E306.
  27. Bermúdez-Silva FJ, Suárez J, Baixeras E, et al. Presence of functional cannabinoid receptors in human endocrine pancreas. Diabetologia. 2008; 51(3): 476–487.
  28. Silvestri C, Di Marzo V. The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. Cell Metab. 2013; 17(4): 475–490.
  29. Evans CO, Young AN, Brown MR, et al. Novel patterns of gene expression in pituitary adenomas identified by complementary deoxyribonucleic acid microarrays and quantitative reverse transcription-polymerase chain reaction. J Clin Endocrinol Metab. 2001; 86(7): 3097–3107.
  30. González S, Bisogno T, Wenger T, et al. Sex steroid influence on cannabinoid CB(1) receptor mRNA and endocannabinoid levels in the anterior pituitary gland. Biochem Biophys Res Commun. 2000; 270(1): 260–266.
  31. González S, Manzanares J, Berrendero F, et al. Identification of endocannabinoids and cannabinoid CB(1) receptor mRNA in the pituitary gland. Neuroendocrinology. 1999; 70(2): 137–145.
  32. Pagotto U, Marsicano G, Fezza F, et al. Normal human pituitary gland and pituitary adenomas express cannabinoid receptor type 1 and synthesize endogenous cannabinoids: first evidence for a direct role of cannabinoids on hormone modulation at the human pituitary level. J Clin Endocrinol Metab. 2001; 86(6): 2687–2696.
  33. Porcella A, Marchese G, Casu MA, et al. Evidence for functional CB1 cannabinoid receptor expressed in the rat thyroid. Eur J Endocrinol. 2002; 147(2): 255–261.
  34. Galiègue S, Mary S, Marchand J, et al. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem. 1995; 232(1): 54–61.
  35. Cani PD, Montoya ML, Neyrinck AM, et al. Potential modulation of plasma ghrelin and glucagon-like peptide-1 by anorexigenic cannabinoid compounds, SR141716A (rimonabant) and oleoylethanolamide. Br J Nutr. 2004; 92(5): 757–761.
  36. Burdyga G, Lal S, Varro A, et al. Expression of cannabinoid CB1 receptors by vagal afferent neurons is inhibited by cholecystokinin. J Neurosci. 2004; 24(11): 2708–2715.
  37. Murphy LL, Newton SC, Dhali J, et al. Evidence for a direct anterior pituitary site of delta-9-tetrahydrocannabinol action. Pharmacol Biochem Behav. 1991; 40(3): 603–607.
  38. Hughes CL, Everett JW, Tyrey L. Delta 9-tetrahydrocannabinol suppression of prolactin secretion in the rat: lack of direct pituitary effect. Endocrinology. 1981; 109(3): 876–880.
  39. Rettori V, Aguila MC, Gimeno MF, et al. In vitro effect of delta 9-tetrahydrocannabinol to stimulate somatostatin release and block that of luteinizing hormone-releasing hormone by suppression of the release of prostaglandin E2. Proc Natl Acad Sci U S A. 1990; 87(24): 10063–10066.
  40. Benowitz NL, Jones RT, Lerner CB. Depression of growth hormone and cortisol response to insulin-induced hypoglycemia after prolonged oral delta-9-tetrahydrocannabinol administration in man. J Clin Endocrinol Metab. 1976; 42(5): 938–941.
  41. Di S, Malcher-Lopes R, Halmos KCs, et al. Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism. J Neurosci. 2003; 23(12): 4850–4857.
  42. Hill MN, Tasker JG. Endocannabinoid signaling, glucocorticoid-mediated negative feedback, and regulation of the hypothalamic-pituitary-adrenal axis. Neuroscience. 2012; 204: 5–16.
  43. Dennedy MC, Friel AM, Houlihan DD, et al. Cannabinoids and the human uterus during pregnancy. Am J Obstet Gynecol. 2004; 190(1): 2–9; discussion 3A.
  44. Wang H, Guo Y, Wang D, et al. Aberrant cannabinoid signaling impairs oviductal transport of embryos. Nat Med. 2004; 10(10): 1074–1080.
  45. Park B, Gibbons HM, Mitchell MD, et al. Identification of the CB1 cannabinoid receptor and fatty acid amide hydrolase (FAAH) in the human placenta. Placenta. 2003; 24(5): 473–478.
  46. Rossato M, Ion Popa F, Ferigo M, et al. Human sperm express cannabinoid receptor Cb1, the activation of which inhibits motility, acrosome reaction, and mitochondrial function. J Clin Endocrinol Metab. 2005; 90(2): 984–991.
  47. Asch RH, Smith CG, Siler-Khodr TM, et al. Effects of delta 9-tetrahydrocannabinol during the follicular phase of the rhesus monkey (Macaca mulatta). J Clin Endocrinol Metab. 1981; 52(1): 50–55.
  48. Bonnin A, Ramos JA, Rodríguez de Fonseca F, et al. Acute effects of delta 9-tetrahydrocannabinol on tuberoinfundibular dopamine activity, anterior pituitary sensitivity to dopamine and prolactin release vary as a function of estrous cycle. Neuroendocrinology. 1993; 58(3): 280–286.
  49. Mendelson JH, Mello NK, Ellingboe J, et al. Marihuana smoking suppresses luteinizing hormone in women. J Pharmacol Exp Ther. 1986; 237(3): 862–866.
  50. Mendelson JH, Cristofaro P, Ellingboe J, et al. Acute effects of marihuana on luteinizing hormone in menopausal women. Pharmacol Biochem Behav. 1985; 23(5): 765–768.
  51. Schuel H, Goldstein E, Mechoulam R, et al. Anandamide (arachidonylethanolamide), a brain cannabinoid receptor agonist, reduces sperm fertilizing capacity in sea urchins by inhibiting the acrosome reaction. Proc Natl Acad Sci U S A. 1994; 91(16): 7678–7682.
  52. Weiss L, Zeira M, Reich S, et al. Cannabidiol lowers incidence of diabetes in non-obese diabetic mice. Autoimmunity. 2006; 39(2): 143–151.
  53. Paria BC, Dey SK. Ligand-receptor signaling with endocannabinoids in preimplantation embryo development and implantation. Chem Phys Lipids. 2000; 108(1–2): 211–220.
  54. Fattore L, Fratta W. How important are sex differences in cannabinoid action? Br J Pharmacol. 2010; 160(3): 544–548.
  55. Piomelli D. THC: moderation during implantation. Nat Med. 2004; 10(1): 19–20.
  56. Lakiotaki E, Giaginis C, Tolia M, et al. Clinical Significance of Cannabinoid Receptors CB1 and CB2 Expression in Human Malignant and Benign Thyroid Lesions. Biomed Res Int. 2015; 2015: 1–7.
  57. Shi Y, Zou M, Baitei EY, et al. Cannabinoid 2 receptor induction by IL-12 and its potential as a therapeutic target for the treatment of anaplastic thyroid carcinoma. Cancer Gene Ther. 2008; 15(2): 101–107.
  58. Nagarkatti P, Pandey R, Rieder SA, et al. Cannabinoids as novel anti-inflammatory drugs. Future Med Chem. 2009; 1(7): 1333–1349.
  59. Brus R, Nowak P. Efekty metaboliczne endogennych kanabinoidów u ssaków. In: Otto-Buczkowska E. ed. Cukrzyca w populacji wieku rozwojowego — co nowego? Cornetis, Wrocław 2009: 55–60.
  60. Sirbu AE, Buburuzan L, Kevorkian S, et al. Adiponectin expression in visceral adiposity is an important determinant of insulin resistance in morbid obesity. Endokrynol Pol. 2018; 69(3): 252–258.
  61. Wojciechowska C, Jacheć W, Romuk E, et al. The effect of BMI, serum leptin, and adiponectin levels on prognosis in patients with non-ischaemic dilated cardiomyopathy. Endokrynol Pol. 2017; 68(1): 26–34.
  62. Bilir BE, Güldiken S, Tunçbilek N, et al. The effects of fat distribution and some adipokines on insulin resistance. Endokrynol Pol. 2016; 67(3): 277–282.
  63. Krysiak R, Żmuda W, Marek B, et al. Age may determine the effect of hypolipidemic agents on plasma adipokine levels in patients with elevated low-density lipoprotein cholesterol levels. Endokrynol Pol. 2016; 67(3): 271–276.
  64. Lafontan M, Piazza PV, Girard J. Effects of CB1 antagonist on the control of metabolic functions in obese type 2 diabetic patients. Diabetes Metab. 2007; 33(2): 85–95.
  65. Pagano C, Pilon C, Calcagno A, et al. The endogenous cannabinoid system stimulates glucose uptake in human fat cells via phosphatidylinositol 3-kinase and calcium-dependent mechanisms. J Clin Endocrinol Metab. 2007; 92(12): 4810–4819.
  66. Pagano C, Rossato M, Vettor R. Endocannabinoids, adipose tissue and lipid metabolism. J Neuroendocrinol. 2008; 20 (Suppl 1): 124–129.
  67. Vettor R, Pagano C. The role of the endocannabinoid system in lipogenesis and fatty acid metabolism. Best Pract Res Clin Endocrinol Metab. 2009; 23(1): 51–63.
  68. Kunos G, Osei-Hyiaman D, Liu J, et al. Endocannabinoids and the Control of Energy Homeostasis. J Biol Chem. 2008; 283(48): 33021–33025.
  69. Bermudez-Silva FJ, Sanchez-Vera I, Suárez J, et al. Role of cannabinoid CB2 receptors in glucose homeostasis in rats. Eur J Pharmacol. 2007; 565(1–3): 207–211.
  70. Bermúdez-Silva FJ, Suárez Pérez J, Nadal A, et al. The role of the pancreatic endocannabinoid system in glucose metabolism. Best Pract Res Clin Endocrinol Metab. 2009; 23(1): 87–102.
  71. Bermúdez-Siva FJ, Serrano A, Diaz-Molina FJ, et al. Activation of cannabinoid CB1 receptors induces glucose intolerance in rats. Eur J Pharmacol. 2006; 531(1–3): 282–284.
  72. Duvivier VF, Delafoy-Plasse L, Delion V, et al. Beneficial effect of a chronic treatment with rimonabant on pancreatic function and beta-cell morphology in Zucker Fatty rats. Eur J Pharmacol. 2009; 616(1–3): 314–320.
  73. Nakata M, Yada T. Cannabinoids inhibit insulin secretion and cytosolic Ca2+ oscillation in islet beta-cells via CB1 receptors. Regul Pept. 2008; 145(1–3): 49–53.
  74. Tharp WG, Lee YH, Maple RL, et al. The cannabinoid CB1 receptor is expressed in pancreatic delta-cells. Biochem Biophys Res Commun. 2008; 372(4): 595–600.
  75. Lipina C, Stretton C, Hastings S, et al. Regulation of MAP kinase-directed mitogenic and protein kinase B-mediated signaling by cannabinoid receptor type 1 in skeletal muscle cells. Diabetes. 2010; 59(2): 375–385.
  76. Saavedra LE. Endocannabinoid system and cardiometabolic risk. Clin Pharmacol Ther. 2007; 82(5): 591–594.
  77. Eckardt K, Sell H, Taube A, et al. Cannabinoid type 1 receptors in human skeletal muscle cells participate in the negative crosstalk between fat and muscle. Diabetologia. 2009; 52(4): 664–674.
  78. Motaghedi R, McGraw TE. The CB1 endocannabinoid system modulates adipocyte insulin sensitivity. Obesity. 2008; 16(8): 1727–1734.
  79. Juan-Picó P, Fuentes E, Bermúdez-Silva FJ, et al. Cannabinoid receptors regulate Ca(2+) signals and insulin secretion in pancreatic beta-cell. Cell Calcium. 2006; 39(2): 155–162.
  80. Linari G, Agostini S, Amadoro G, et al. Involvement of cannabinoid CB1- and CB2-receptors in the modulation of exocrine pancreatic secretion. Pharmacol Res. 2009; 59(3): 207–214.
  81. Zhang F, Hong S, Stone V, et al. Expression of cannabinoid CB1 receptors in models of diabetic neuropathy. J Pharmacol Exp Ther. 2007; 323(2): 508–515.
  82. Toth C, Jedrzejewski N, Ellis C, et al. Cannabinoid-Mediated Modulation of Neuropathic Pain and Microglial Accumulation in a Model of Murine Type I Diabetic Peripheral Neuropathic Pain. Molecular Pain. 2010; 6: 16.
  83. Fride E, Bregman T, Kirkham TC. Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood. Exp Biol Med (Maywood). 2005; 230(4): 225–234.
  84. Díaz-Asensio C, Setién R, Echevarría E, et al. Type 1 diabetes alters brain cannabinoid receptor expression and phosphorylation status in rats. Horm Metab Res. 2008; 40(7): 454–458.
  85. Davis SN, Perkins JM. Role of the endocannabinoid system in management of patients with type 2 diabetes mellitus and cardiovascular risk factors. Endocr Pract. 2007; 13(7): 790–804.
  86. Di Marzo V. The endocannabinoid system in obesity and type 2 diabetes. Diabetologia. 2008; 51(8): 1356–1367.
  87. Janero DR, Makriyannis A. Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis. Expert Opin Emerg Drugs. 2009; 14(1): 43–65.
  88. Scheen AJ, Paquot N. Use of cannabinoid CB1 receptor antagonists for the treatment of metabolic disorders. Best Pract Res Clin Endocrinol Metab. 2009; 23(1): 103–116.
  89. Scheen AJ. The endocannabinoid system: a promising target for the management of type 2 diabetes. Curr Protein Pept Sci. 2009; 10(1): 56–74.
  90. Rutkowska M, Jamontt J. Involvement of the Cannabinoid System in the Regulation of Food Intake. Adv Clin Exp Med. 2005; 14: 1011–1017.
  91. Kozakowski J, Zgliczyński W. Rola układu endokannabinoidowego w patogenezie otyłości. Post Nauk Med. 2008; 3: 198–202.
  92. Jamshidi N, Taylor DA. Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats. Br J Pharmacol. 2001; 134(6): 1151–1154.
  93. Kirkham TC, Williams CM, Fezza F, et al. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br J Pharmacol. 2002; 136(4): 550–557.
  94. Siebenhofer A, Jeitler K, Horvath K, et al. Long-term effects of weight-reducing drugs in people with hypertension. Cochrane Database Syst Rev. 2016; 3: CD007654.
  95. Wathion N. Public statement on Acomplia (rimonabant). Withdrawal of the marketing authorisation in the European Union. EMEA. 2009; 30: 1.
  96. Jung UnJu, Choi MS. Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci. 2014; 15(4): 6184–6223.
  97. Di Marzo V, Goparaju SK, Wang L, et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature. 2001; 410(6830): 822–825.
  98. Bruinsma K, Taren DL. Chocolate: food or drug? J Am Diet Assoc. 1999; 99(10): 1249–1256.
  99. Nocerino E, Amato M, Izzo AA. Cannabis and cannabinoid receptors. Fitoterapia. 2000; 71(Suppl 1): 6–12.
  100. Fride E, Foox A, Rosenberg E, et al. Milk intake and survival in newborn cannabinoid CB1 receptor knockout mice: evidence for a. Eur J Pharmacol. 2003; 461(1): 27–34.
  101. Di Marzo V, Sepe N, De Petrocellis L, et al. Trick or treat from food endocannabinoids? Nature. 1998; 396(6712): 636–637.
  102. Birdsall SM, Birdsall TC, Tims LA. The Use of Medical Marijuana in Cancer. Curr Oncol Rep. 2016; 18(7): 40.
  103. Blickman T. Cannabis policy reform in Europe. Bottom up rather than top down. Transnational institute, Series on Legislative Reform of Drug Policies No. TNI. 2014(28): 1–24.
  104. Szulc M. Konsekwencje zdrowotne używania marihuany w świetle badań oraz propozycja ujednolicenia stanowiska psychologów wobec problemu legalizacji konopi, sformułowana w oparciu o Kodeks Etyczno-Zawodowy Psychologa. Alkoholizm i Narkomania. 2013; 26(4): 381–401.
  105. Kalant H. Cannabis control policy: No rational basis yet for legalization. Clin Pharmacol Ther. 2015; 97(6): 538–540.
  106. Jones RT, Jones RT. Marijuana. Health and treatment issues. Psychiatr Clin North Am. 1984; 7(4): 703–712.
  107. Randall MD, Harris D, Kendall DA, et al. Cardiovascular effects of cannabinoids. Pharmacol Ther. 2002; 95(2): 191–202.
  108. Maccarrone M, Finazzi-Agrò A. Anandamide hydrolase: a guardian angel of human reproduction? Trends Pharmacol Sci. 2004; 25(7): 353–357.
  109. Struwe M, Kaempfer SH, Geiger CJ, et al. Effect of dronabinol on nutritional status in HIV infection. Ann Pharmacother. 1993; 27(7-8): 827–831.
  110. Ahmed A, van der Marck MA, van den Elsen G, et al. Cannabinoids in late-onset Alzheimer's disease. Clin Pharmacol Ther. 2015; 97(6): 597–606.
  111. Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012; 2: e94.
  112. Szaflarski JP, Bebin EM. Cannabis, cannabidiol, and epilepsy — from receptors to clinical response. Epilepsy Behav. 2014; 41: 277–282.
  113. Friedman D, Devinsky O. Cannabinoids in the Treatment of Epilepsy. N Engl J Med. 2015; 373(11): 1048–1058.
  114. Tzadok M, Uliel-Siboni S, Linder I, et al. CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience. Seizure. 2016; 35: 41–44.
  115. Bolognini D, Ross RA. Medical cannabis vs. synthetic cannabinoids: What does the future hold? Clin Pharmacol Ther. 2015; 97(6): 568–570.
  116. Patti F, Messina S, Solaro C, et al. SA.FE. study group. Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity. J Neurol Neurosurg Psychiatry. 2016; 87(9): 944–951.
  117. Merari A, Barak A, Plaves M. Effects of 1(2) tetrahydrocannabinol on copulation in the male rat. Psychopharmacologia. 1973; 28(3): 243–246.
  118. Sipe JC, Waalen J, Gerber A, et al. Overweight and obesity associated with a missense polymorphism in fatty acid amide hydrolase (FAAH). Int J Obes (Lond). 2005; 29(7): 755–759.
  119. Symons AM, Teale JD, Marks V. Proceedings: Effect of delta9-tetrahydrocannabinol on the hypothalamic-pituitary-gonadal system in the maturing male rat. J Endocrinol. 1976; 68(3): 43–44.
  120. Tsou K, Brown S, Sañudo-Peña MC, et al. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience. 1998; 83(2): 393–411.
  121. Tzavara ET, Li DL, Moutsimilli L, et al. Endocannabinoids activate transient receptor potential vanilloid 1 receptors to reduce hyperdopaminergia-related hyperactivity: therapeutic implications. Biol Psychiatry. 2006; 59(6): 508–515.
  122. Van Gaal LF, Rissanen AM, Scheen AJ, et al. RIO-Europe Study Group. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet. 2005; 365(9468): 1389–1397.