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Medical Use of Cannabinoids

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Abstract

Cannabinoid receptors, endocannabinoids and the enzymes responsible for their biosynthesis and degradation constitute the endocannabinoid system. In recent decades, the endocannabinoid system has attracted considerable interest as a potential therapeutic target in numerous pathological conditions. Its involvement in several physiological processes is well known, such as in energy balance, appetite stimulation, blood pressure, pain modulation, embryogenesis, nausea and vomiting control, memory, learning and immune response, among others, as well as in pathological conditions where it exerts a protective role in the development of certain disorders. As a result, it has been reported that changes in endocannabinoid levels may be related to neurological diseases such as Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and multiple sclerosis, as well as anorexia and irritable bowel syndrome. Alterations in the endocannabinoid system have also been associated with cancer, affecting the growth, migration and invasion of some tumours. Cannabinoids have been tested in several cancer types, including brain, breast and prostate cancers. Cannabinoids have shown promise as analgesics for the treatment of both inflammatory and neuropathic pain. There is also evidence for a role of the endocannabinoid system in the control of emotional states, and cannabinoids could prove useful in decreasing and palliating post-traumatic stress disorder symptoms and anxiolytic disorders. The role of the endocannabinoid system in addictions has also been examined, and cannabinoids have been postulated as alternative and co-adjuvant treatments in some abuse syndromes, mainly in ethanol and opioid abuses. The expression of the endocannabinoid system in the eye suggests that it could be a potential therapeutic target for eye diseases. Considering the importance of the endocannabinoid system and the therapeutic potential of cannabinoids in this vast number of medical conditions, several clinical studies with cannabinoid-based medications are ongoing. In addition, some cannabinoid-based medications have already been approved in various countries, including nabilone and dronabinol capsules for the treatment of nausea and vomiting associated with chemotherapy, dronabinol capsules for anorexia, an oral solution of dronabinol for both vomiting associated with chemotherapy and anorexia, a Δ9-tetrahydrocannabinol/cannabidiol oromucosal spray for pain related to cancer and for spasticity and pain associated with multiple sclerosis, and an oral solution of cannabidiol for Dravet and Lennox–Gastaut syndromes. Here, we review the available efficacy, safety and tolerability data for cannabinoids in a range of medical conditions.

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References

  1. Maule WJ. Medical uses of marijuana (Cannabis sativa): fact or fallacy? Br J Biomed Sci. 2015;72(2):85–91.

    Article  CAS  PubMed  Google Scholar 

  2. Zuardi AW. History of cannabis as a medicine: a review. Rev Bras Psiquiatr. 2006;28(2):153–7. https://doi.org/10.1590/S1516-44462006000200015.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Kalant H. Medicinal use of cannabis: history and current status. Pain Res Manag. 2001;6(2):80–91.

    Article  CAS  PubMed  Google Scholar 

  5. Mikuriya TH. Marijuana in medicine: past, present and future. Calif Med. 1969;110(1):34–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Pisanti S, Bifulco M. Modern history of medical cannabis: from widespread use to prohibitionism and back. Trends Pharmacol Sci. 2017;38(3):195–8. https://doi.org/10.1016/j.tips.2016.12.002.

    Article  CAS  PubMed  Google Scholar 

  7. Mechoulam R. Cannabinoids as therapeutic agents. Boca Raton: CRC Press; 1986.

    Google Scholar 

  8. Svizenska I, Dubovy P, Sulcova A. Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligands and functional involvement in nervous system structures: a short review. Pharmacol Biochem Behav. 2008;90(4):501–11. https://doi.org/10.1016/j.pbb.2008.05.010.

    Article  CAS  PubMed  Google Scholar 

  9. Console-Bram L, Marcu J, Abood ME. Cannabinoid receptors: nomenclature and pharmacological principles. Prog Neuropsychopharmacol Biol Psychiatry. 2012;38(1):4–15. https://doi.org/10.1016/j.pnpbp.2012.02.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Szulakowska A, Milnerowicz H. Cannabis sativa in the light of scientific research. Adv Clin Exp Med. 2007;16(6):807–15.

    Google Scholar 

  11. Kendall DA, Yudowski GA. Cannabinoid receptors in the central nervous system: their signaling and roles in disease. Front Cell Neurosci. 2016;10:294. https://doi.org/10.3389/fncel.2016.00294.

    Article  CAS  PubMed  Google Scholar 

  12. Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, et al. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science. 2005;310(5746):329–32. https://doi.org/10.1126/science.1115740.

    Article  CAS  PubMed  Google Scholar 

  13. Onaivi ES, Ishiguro H, Gong JP, Patel S, Perchuk A, Meozzi PA, et al. Discovery of the presence and functional expression of cannabinoid CB2 receptors in brain. Ann N Y Acad Sci. 2006;1074:514–36. https://doi.org/10.1196/annals.1369.052.

    Article  CAS  PubMed  Google Scholar 

  14. Henstridge CM. Off-target cannabinoid effects mediated by GPR55. Pharmacology. 2012;89(3–4):179–87. https://doi.org/10.1159/000336872.

    Article  CAS  PubMed  Google Scholar 

  15. Bisogno T, Howell F, Williams G, Minassi A, Cascio MG, Ligresti A, et al. Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol. 2003;163(3):463–8. https://doi.org/10.1083/jcb.200305129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bisogno T, Melck D, De Petrocellis L, Di Marzo V. Phosphatidic acid as the biosynthetic precursor of the endocannabinoid 2-arachidonoylglycerol in intact mouse neuroblastoma cells stimulated with ionomycin. J Neurochem. 1999;72(5):2113–9.

    Article  CAS  PubMed  Google Scholar 

  17. Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature. 1996;384(6604):83–7. https://doi.org/10.1038/384083a0.

    Article  CAS  PubMed  Google Scholar 

  18. Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci USA. 2002;99(16):10819–24. https://doi.org/10.1073/pnas.152334899.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fraguas-Sánchez AI, Fernández-Carballido A, Torres-Suárez AI. Phyto-, endo- and synthetic cannabinoids: promising chemotherapeutic agents in the treatment of breast and prostate carcinomas. Expert Opin Investig Drugs. 2016;25(11):1311–23. https://doi.org/10.1080/13543784.2016.1236913.

    Article  CAS  PubMed  Google Scholar 

  20. Schurman LD, Lichtman AH. Endocannabinoids: a promising impact for traumatic brain injury. Front Pharmacol. 2017;8:69. https://doi.org/10.3389/fphar.2017.00069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev. 2006;27(1):73–100. https://doi.org/10.1210/er.2005-0009.

    Article  CAS  PubMed  Google Scholar 

  22. Cunha P, Romão AM, Mascarenhas-Melo F, Teixeira HM, Reis F. Endocannabinoid system in cardiovascular disorders: new pharmacotherapeutic opportunities. J Pharm Bioallied Sci. 2011;3(3):350–60. https://doi.org/10.4103/0975-7406.84435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Katchan V, David P, Shoenfeld Y. Cannabinoids and autoimmune diseases: a systematic review. Autoimmun Rev. 2016;15(6):513–28. https://doi.org/10.1016/j.autrev.2016.02.008.

    Article  CAS  PubMed  Google Scholar 

  24. Laprairie RB, Bagher AM, Denovan-Wright EM. Cannabinoid receptor ligand bias: implications in the central nervous system. Curr Opin Pharmacol. 2017;32:32–43. https://doi.org/10.1016/j.coph.2016.10.005.

    Article  CAS  PubMed  Google Scholar 

  25. Di Marzo V. Targeting the endocannabinoid system: to enhance or reduce? Nat Rev Drug Discov. 2008;7(5):438–55.

    Article  PubMed  CAS  Google Scholar 

  26. Pacher P, Mechoulam R. Is lipid signaling through cannabinoid 2 receptors part of a protective system? Prog Lipid Res. 2011;50(2):193–211. https://doi.org/10.1016/j.plipres.2011.01.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hasenoehrl C, Taschler U, Storr M, Schicho R. The gastrointestinal tract: a central organ of cannabinoid signaling in health and disease. Neurogastroenterol Motil. 2016;28(12):1765–80. https://doi.org/10.1111/nmo.12931.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ligresti A, De Petrocellis L, Di Marzo V. From phytocannabinoids to cannabinoid receptors and endocannabinoids: pleiotropic physiological and pathological roles through complex pharmacology. Physiol Rev. 2016;96(4):1593–659. https://doi.org/10.1152/physrev.00002.2016.

    Article  CAS  PubMed  Google Scholar 

  29. Bridgeman MB, Abazia DT. Medicinal cannabis: history, pharmacology, and implications for the acute care setting. Pharm Ther. 2017;42(3):180–8.

    Google Scholar 

  30. Pyszniak M, Tabarkiewicz J, Luszczki JJ. Endocannabinoid system as a regulator of tumor cell malignancy: biological pathways and clinical significance. Onco Targets Ther. 2016;9:4323–36. https://doi.org/10.2147/ott.s106944.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pertwee RG. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philos Trans R Soc Lond B Biol Sci. 2012;367(1607):3353–63. https://doi.org/10.1098/rstb.2011.0381.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nikan M, Nabavi SM, Manayi A. Ligands for cannabinoid receptors, promising anticancer agents. Life Sci. 2016;146:124–30. https://doi.org/10.1016/j.lfs.2015.12.053.

    Article  CAS  PubMed  Google Scholar 

  33. Tegeder I. Endocannabinoids as guardians of metastasis. Int J Mol Sci. 2016;17(2):230. https://doi.org/10.3390/ijms17020230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Benito C, Romero JP, Tolon RM, Clemente D, Docagne F, Hillard CJ, et al. Cannabinoid CB1 and CB2 receptors and fatty acid amide hydrolase are specific markers of plaque cell subtypes in human multiple sclerosis. J Neurosci. 2007;27(9):2396–402. https://doi.org/10.1523/jneurosci.4814-06.2007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jean-Gilles L, Feng S, Tench CR, Chapman V, Kendall DA, Barrett DA, et al. Plasma endocannabinoid levels in multiple sclerosis. J Neurol Sci. 2009;287(1–2):212–5. https://doi.org/10.1016/j.jns.2009.07.021.

    Article  CAS  PubMed  Google Scholar 

  36. Centonze D, Bari M, Rossi S, Prosperetti C, Furlan R, Fezza F, et al. The endocannabinoid system is dysregulated in multiple sclerosis and in experimental autoimmune encephalomyelitis. Brain. 2007;130(Pt 10):2543–53. https://doi.org/10.1093/brain/awm160.

    Article  PubMed  Google Scholar 

  37. Sanchez Lopez AJ, Roman-Vega L, Ramil Tojeiro E, Giuffrida A, Garcia-Merino A. Regulation of cannabinoid receptor gene expression and endocannabinoid levels in lymphocyte subsets by interferon-beta: a longitudinal study in multiple sclerosis patients. Clin Exp Immunol. 2015;179(1):119–27. https://doi.org/10.1111/cei.12443.

    Article  CAS  PubMed  Google Scholar 

  38. Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG, Makriyannis A, et al. Endocannabinoids control spasticity in a multiple sclerosis model. FASEB J. 2001;15(2):300–2. https://doi.org/10.1096/fj.00-0399fje.

    Article  CAS  PubMed  Google Scholar 

  39. Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG, Huffman JW, et al. Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature. 2000;404(6773):84–7. https://doi.org/10.1038/35003583.

    Article  CAS  PubMed  Google Scholar 

  40. Pryce G, Baker D. Control of spasticity in a multiple sclerosis model is mediated by CB1, not CB2, cannabinoid receptors. Br J Pharmacol. 2007;150(4):519–25. https://doi.org/10.1038/sj.bjp.0707003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pryce G, Cabranes A, Fernandez-Ruiz J, Bisogno T, Di Marzo V, Long JZ, et al. Control of experimental spasticity by targeting the degradation of endocannabinoids using selective fatty acid amide hydrolase inhibitors. Mult Scler. 2013;19(14):1896–904. https://doi.org/10.1177/1352458513485982.

    Article  CAS  PubMed  Google Scholar 

  42. Bernal-Chico A, Canedo M, Manterola A, Victoria Sanchez-Gomez M, Perez-Samartin A, Rodriguez-Puertas R, et al. Blockade of monoacylglycerol lipase inhibits oligodendrocyte excitotoxicity and prevents demyelination in vivo. Glia. 2015;63(1):163–76. https://doi.org/10.1002/glia.22742.

    Article  PubMed  Google Scholar 

  43. Hernandez-Torres G, Cipriano M, Heden E, Bjorklund E, Canales A, Zian D, et al. A reversible and selective inhibitor of monoacylglycerol lipase ameliorates multiple sclerosis. Angew Chem Int Ed Engl. 2014;53(50):13765–70. https://doi.org/10.1002/anie.201407807.

    Article  CAS  PubMed  Google Scholar 

  44. Feliu A, Bonilla Del Rio I, Carrillo-Salinas FJ, Hernandez-Torres G. 2-Arachidonoylglycerol reduces proteoglycans and enhances remyelination in a progressive model of demyelination. J Neurosci. 2017;37(35):8385–98. https://doi.org/10.1523/jneurosci.2900-16.2017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Elliott DM, Singh N, Nagarkatti M, Nagarkatti PS. Cannabidiol attenuates experimental autoimmune encephalomyelitis model of multiple sclerosis through induction of myeloid-derived suppressor cells. Front Immunol. 2018;9:1782. https://doi.org/10.3389/fimmu.2018.01782.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Killestein J, Hoogervorst EL, Reif M, Kalkers NF, Van Loenen AC, Staats PG, et al. Safety, tolerability, and efficacy of orally administered cannabinoids in MS. Neurology. 2002;58(9):1404–7.

    Article  CAS  PubMed  Google Scholar 

  47. Ungerleider JT, Andyrsiak T, Fairbanks L, Ellison GW, Myers LW. Delta-9-THC in the treatment of spasticity associated with multiple sclerosis. Adv Alcohol Subst Abuse. 1987;7(1):39–50.

    Article  CAS  PubMed  Google Scholar 

  48. Zajicek J, Fox P, Sanders H, Wright D, Vickery J, Nunn A, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet. 2003;362(9395):1517–26. https://doi.org/10.1016/s0140-6736(03)14738-1.

    Article  CAS  PubMed  Google Scholar 

  49. Zajicek JP, Sanders HP, Wright DE, Vickery PJ, Ingram WM, Reilly SM, et al. Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. J Neurol Neurosurg Psychiatry. 2005;76(12):1664–9. https://doi.org/10.1136/jnnp.2005.070136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zajicek JP, Hobart JC, Slade A, Barnes D, Mattison PG. Multiple sclerosis and extract of cannabis: results of the MUSEC trial. J Neurol Neurosurg Psychiatry. 2012;83(11):1125–32. https://doi.org/10.1136/jnnp-2012-302468.

    Article  PubMed  Google Scholar 

  51. Wade DT, Makela P, Robson P, House H, Bateman C. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Mult Scler. 2004;10(4):434–41. https://doi.org/10.1191/1352458504ms1082oa.

    Article  CAS  PubMed  Google Scholar 

  52. Collin C, Davies P, Mutiboko IK, Ratcliffe S. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur J Neurol. 2007;14(3):290–6. https://doi.org/10.1111/j.1468-1331.2006.01639.x.

    Article  CAS  PubMed  Google Scholar 

  53. Collin C, Ehler E, Waberzinek G, Alsindi Z, Davies P, Powell K, et al. A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Neurol Res. 2010;32(5):451–9. https://doi.org/10.1179/016164109x12590518685660.

    Article  CAS  PubMed  Google Scholar 

  54. Notcutt W, Langford R, Davies P, Ratcliffe S, Potts R. A placebo-controlled, parallel-group, randomized withdrawal study of subjects with symptoms of spasticity due to multiple sclerosis who are receiving long-term Sativex® (nabiximols). Mult Scler. 2012;18(2):219–28. https://doi.org/10.1177/1352458511419700.

    Article  CAS  PubMed  Google Scholar 

  55. Novotna A, Mares J, Ratcliffe S, Novakova I, Vachova M, Zapletalova O, et al. A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex®), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Eur J Neurol. 2011;18(9):1122–31. https://doi.org/10.1111/j.1468-1331.2010.03328.x.

    Article  CAS  PubMed  Google Scholar 

  56. Rog DJ, Nurmikko TJ, Friede T, Young CA. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology. 2005;65(6):812–9. https://doi.org/10.1212/01.wnl.0000176753.45410.8b.

    Article  PubMed  Google Scholar 

  57. Rog DJ, Nurmikko TJ, Young CA. Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial. Clin Ther. 2007;29(9):2068–79. https://doi.org/10.1016/j.clinthera.2007.09.013.

    Article  CAS  PubMed  Google Scholar 

  58. Brady CM, DasGupta R, Dalton C, Wiseman OJ, Berkley KJ, Fowler CJ. An open-label pilot study of cannabis-based extracts for bladder dysfunction in advanced multiple sclerosis. Mult Scler. 2004;10(4):425–33. https://doi.org/10.1191/1352458504ms1063oa.

    Article  CAS  PubMed  Google Scholar 

  59. Freeman RM, Adekanmi O, Waterfield MR, Waterfield AE, Wright D, Zajicek J. The effect of cannabis on urge incontinence in patients with multiple sclerosis: a multicentre, randomised placebo-controlled trial (CAMS-LUTS). Int Urogynecol J Pelvic Floor Dysfunct. 2006;17(6):636–41. https://doi.org/10.1007/s00192-006-0086-x.

    Article  CAS  PubMed  Google Scholar 

  60. Kavia RB, De Ridder D, Constantinescu CS, Stott CG, Fowler CJ. Randomized controlled trial of Sativex to treat detrusor overactivity in multiple sclerosis. Mult Scler. 2010;16(11):1349–59. https://doi.org/10.1177/1352458510378020.

    Article  CAS  PubMed  Google Scholar 

  61. Arevalo-Martin A, Vela JM, Molina-Holgado E, Borrell J, Guaza C. Therapeutic action of cannabinoids in a murine model of multiple sclerosis. J Neurosci. 2003;23(7):2511–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Croxford JL, Miller SD. Immunoregulation of a viral model of multiple sclerosis using the synthetic cannabinoid R + WIN55,212. J Clin Investig. 2003;111(8):1231–40. https://doi.org/10.1172/jci17652.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Killestein J, Hoogervorst EL, Reif M, Blauw B, Smits M, Uitdehaag BM, et al. Immunomodulatory effects of orally administered cannabinoids in multiple sclerosis. J Neuroimmunol. 2003;137(1–2):140–3.

    Article  CAS  PubMed  Google Scholar 

  64. Zajicek J, Ball S, Wright D, Vickery J, Nunn A, Miller D, et al. Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial. Lancet Neurol. 2013;12(9):857–65. https://doi.org/10.1016/s1474-4422(13)70159-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, et al. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science. 2003;302(5642):84–8. https://doi.org/10.1126/science.1088208.

    Article  CAS  PubMed  Google Scholar 

  66. Wallace MJ, Blair RE, Falenski KW, Martin BR, DeLorenzo RJ. 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. https://doi.org/10.1124/jpet.103.051920.

    Article  CAS  PubMed  Google Scholar 

  67. Karanian DA, Karim SL, Wood JT, Williams JS, Lin S, Makriyannis A, et al. Endocannabinoid enhancement protects against kainic acid-induced seizures and associated brain damage. J Pharmacol Exp Ther. 2007;322(3):1059–66. https://doi.org/10.1124/jpet.107.120147.

    Article  CAS  PubMed  Google Scholar 

  68. Naidoo V, Karanian DA, Vadivel SK, Locklear JR, Wood JT, Nasr M, et al. Equipotent inhibition of fatty acid amide hydrolase and monoacylglycerol lipase: dual targets of the endocannabinoid system to protect against seizure pathology. Neurotherapeutics. 2012;9(4):801–13. https://doi.org/10.1007/s13311-011-0100-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Shirzadian A, Ostadhadi S, Hassanipour M, Shafaroodi H, Khoshnoodi M, Haj-Mirzaian A, et al. Acute foot-shock stress decreased seizure susceptibility against pentylenetetrazole-induced seizures in mice: interaction between endogenous opioids and cannabinoids. Epilepsy Behav. 2018;87:25–31. https://doi.org/10.1016/j.yebeh.2018.06.035.

    Article  PubMed  Google Scholar 

  70. Hill AJ, Mercier MS, Hill TD, Glyn SE, Jones NA, Yamasaki Y, et al. Cannabidivarin is anticonvulsant in mouse and rat. Br J Pharmacol. 2012;167(8):1629–42. https://doi.org/10.1111/j.1476-5381.2012.02207.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Amada N, Yamasaki Y, Williams CM, Whalley BJ. Cannabidivarin (CBDV) suppresses pentylenetetrazole (PTZ)-induced increases in epilepsy-related gene expression. PeerJ. 2013;1:e214. https://doi.org/10.7717/peerj.214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hill TD, Cascio MG, Romano B, Duncan M, Pertwee RG, Williams CM, 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. https://doi.org/10.1111/bph.12321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Iannotti FA, Hill CL, Leo A, Alhusaini A, Soubrane C, Mazzarella E, et al. 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. 2014;5(11):1131–41. https://doi.org/10.1021/cn5000524.

    Article  CAS  PubMed  Google Scholar 

  74. Ellison JM, Gelwan E, Ogletree J. Complex partial seizure symptoms affected by marijuana abuse. J Clin Psychiatry. 1990;51(10):439–40.

    CAS  PubMed  Google Scholar 

  75. Mortati K, Dworetzky B, Devinsky O. Marijuana: an effective antiepileptic treatment in partial epilepsy? A case report and review of the literature. Rev Neurol Dis. 2007;4(2):103–6.

    PubMed  Google Scholar 

  76. Gross DW, Hamm J, Ashworth NL, Quigley D. Marijuana use and epilepsy: prevalence in patients of a tertiary care epilepsy center. Neurology. 2004;62(11):2095–7.

    Article  CAS  PubMed  Google Scholar 

  77. Hamerle M, Ghaeni L, Kowski A, Weissinger F, Holtkamp M. Cannabis and other illicit drug use in epilepsy patients. Eur J Neurol. 2014;21(1):167–70. https://doi.org/10.1111/ene.12081.

    Article  CAS  PubMed  Google Scholar 

  78. 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. https://doi.org/10.1016/j.yebeh.2013.08.037.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Hussain SA, Zhou R, Jacobson C, Weng J, Cheng E, Lay J, et al. Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: a potential role for infantile spasms and Lennox–Gastaut syndrome. Epilepsy Behav. 2015;47:138–41. https://doi.org/10.1016/j.yebeh.2015.04.009.

    Article  PubMed  Google Scholar 

  80. Tzadok M, Uliel-Siboni S, Linder I, Kramer U, Epstein O, Menascu S, et al. CBD-enriched medical cannabis for intractable pediatric epilepsy: the current Israeli experience. Seizure. 2016;35:41–4. https://doi.org/10.1016/j.seizure.2016.01.004.

    Article  PubMed  Google Scholar 

  81. 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. https://doi.org/10.1016/j.yebeh.2015.02.043.

    Article  PubMed  Google Scholar 

  82. Treat L, Chapman KE, Colborn KL, Knupp KG. Duration of use of oral cannabis extract in a cohort of pediatric epilepsy patients. Epilepsia. 2017;58(1):123–7. https://doi.org/10.1111/epi.13617.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  84. Gofshteyn JS, Wilfong A, Devinsky O, Bluvstein J, Charuta J, Ciliberto MA, et al. Cannabidiol as a potential treatment for febrile infection-related epilepsy syndrome (FIRES) in the acute and chronic phases. J Child Neurol. 2017;32(1):35–40. https://doi.org/10.1177/0883073816669450.

    Article  PubMed  Google Scholar 

  85. Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376(21):2011–20. https://doi.org/10.1056/NEJMoa1611618.

    Article  CAS  PubMed  Google Scholar 

  86. Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016;15(3):270–8. https://doi.org/10.1016/s1474-4422(15)00379-8.

    Article  CAS  PubMed  Google Scholar 

  87. Suraev A, Lintzeris N, Stuart J, Kevin RC, Blackburn R, Richards E, et al. Composition and use of cannabis extracts for childhood eilepsy in the Australian community. Sci Rep. 2018;8(1):10154. https://doi.org/10.1038/s41598-018-28127-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. O’Connell BK, Gloss D, Devinsky O. Cannabinoids in treatment-resistant epilepsy: a review. Epilepsy Behav. 2017;70(Pt B):341–8. https://doi.org/10.1016/j.yebeh.2016.11.012.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  90. Stampanoni Bassi M, Sancesario A, Morace R, Centonze D, Iezzi E. Cannabinoids in Parkinson’s disease. Cannabis Cannabinoid Res. 2017;2(1):21–9. https://doi.org/10.1089/can.2017.0002.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Basavarajappa BS, Shivakumar M, Joshi V, Subbanna S. Endocannabinoid system in neurodegenerative disorders. J Neurochem. 2017;142(5):624–48. https://doi.org/10.1111/jnc.14098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Hurley MJ, Mash DC, Jenner P. Expression of cannabinoid CB1 receptor mRNA in basal ganglia of normal and parkinsonian human brain. J Neural Transm (Vienna). 2003;110(11):1279–88. https://doi.org/10.1007/s00702-003-0033-7.

    Article  CAS  PubMed  Google Scholar 

  93. Pisani A, Fezza F, Galati S, Battista N, Napolitano S, Finazzi-Agro A, et al. High endogenous cannabinoid levels in the cerebrospinal fluid of untreated Parkinson’s disease patients. Ann Neurol. 2005;57(5):777–9. https://doi.org/10.1002/ana.20462.

    Article  PubMed  Google Scholar 

  94. Gubellini P, Picconi B, Bari M, Battista N, Calabresi P, Centonze D, et al. Experimental parkinsonism alters endocannabinoid degradation: implications for striatal glutamatergic transmission. J Neurosci. 2002;22(16):6900–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Fernandez-Suarez D, Celorrio M, Riezu-Boj JI, Ugarte A, Pacheco R, Gonzalez H, et al. Monoacylglycerol lipase inhibitor JZL184 is neuroprotective and alters glial cell phenotype in the chronic MPTP mouse model. Neurobiol Aging. 2014;35(11):2603–16. https://doi.org/10.1016/j.neurobiolaging.2014.05.021.

    Article  CAS  PubMed  Google Scholar 

  96. Celorrio M, Fernandez-Suarez D, Rojo-Bustamante E, Echeverry-Alzate V, Ramirez MJ, Hillard CJ, et al. Fatty acid amide hydrolase inhibition for the symptomatic relief of Parkinson’s disease. Brain Behav Immun. 2016;57:94–105. https://doi.org/10.1016/j.bbi.2016.06.010.

    Article  CAS  PubMed  Google Scholar 

  97. Viveros-Paredes JM, Gonzalez-Castaneda RE, Escalante-Castaneda A, Tejeda-Martinez AR, Castaneda-Achutigui F, Flores-Soto ME. Effect of inhibition of fatty acid amide hydrolase on MPTP-induced dopaminergic neuronal damage. Neurologia. 2017. https://doi.org/10.1016/j.nrl.2016.11.008 (Epub ahead of print).

    Article  PubMed  Google Scholar 

  98. El-Banoua F, Caraballo I, Flores JA, Galan-Rodriguez B, Fernandez-Espejo E. Effects on turning of microinjections into basal ganglia of D(1) and D(2) dopamine receptors agonists and the cannabinoid CB(1) antagonist SR141716A in a rat Parkinson’s model. Neurobiol Dis. 2004;16(2):377–85. https://doi.org/10.1016/j.nbd.2004.03.002.

    Article  CAS  PubMed  Google Scholar 

  99. González S, Scorticati C, Garcia-Arencibia M, de Miguel R, Ramos JA, Fernandez-Ruiz J. Effects of rimonabant, a selective cannabinoid CB1 receptor antagonist, in a rat model of Parkinson’s disease. Brain Res. 2006;1073–1074:209–19. https://doi.org/10.1016/j.brainres.2005.12.014.

    Article  CAS  PubMed  Google Scholar 

  100. Kelsey JE, Harris O, Cassin J. The CB(1) antagonist rimonabant is adjunctively therapeutic as well as monotherapeutic in an animal model of Parkinson’s disease. Behav Brain Res. 2009;203(2):304–7. https://doi.org/10.1016/j.bbr.2009.04.035.

    Article  CAS  PubMed  Google Scholar 

  101. Garcia C, Palomo-Garo C, Garcia-Arencibia M, Ramos J, Pertwee R, Fernandez-Ruiz J. Symptom-relieving and neuroprotective effects of the phytocannabinoid delta(9)-THCV in animal models of Parkinson’s disease. Br J Pharmacol. 2011;163(7):1495–506. https://doi.org/10.1111/j.1476-5381.2011.01278.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Meschler JP, Howlett AC, Madras BK. Cannabinoid receptor agonist and antagonist effects on motor function in normal and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)-treated non-human primates. Psychopharmacology (Berl). 2001;156(1):79–85.

    Article  CAS  PubMed  Google Scholar 

  103. Mesnage V, Houeto JL, Bonnet AM, Clavier I, Arnulf I, Cattelin F, et al. Neurokinin B, neurotensin, and cannabinoid receptor antagonists and Parkinson disease. Clin Neuropharmacol. 2004;27(3):108–10.

    Article  CAS  PubMed  Google Scholar 

  104. Carroll CB, Bain PG, Teare L, Liu X, Joint C, Wroath C, et al. Cannabis for dyskinesia in Parkinson disease: a randomized double-blind crossover study. Neurology. 2004;63(7):1245–50.

    Article  CAS  PubMed  Google Scholar 

  105. Chagas MH, Zuardi AW, Tumas V, Pena-Pereira MA, Sobreira ET, Bergamaschi MM, et al. Effects of cannabidiol in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial. J Psychopharmacol. 2014;28(11):1088–98. https://doi.org/10.1177/0269881114550355.

    Article  CAS  PubMed  Google Scholar 

  106. Zuardi AW, Crippa JA, Hallak JE, Pinto JP, Chagas MH, Rodrigues GG, et al. Cannabidiol for the treatment of psychosis in Parkinson’s disease. J Psychopharmacol. 2009;23(8):979–83. https://doi.org/10.1177/0269881108096519.

    Article  CAS  PubMed  Google Scholar 

  107. Chagas MH, Eckeli AL, Zuardi AW, Pena-Pereira MA, Sobreira-Neto MA, Sobreira ET, et al. Cannabidiol can improve complex sleep-related behaviours associated with rapid eye movement sleep behaviour disorder in Parkinson’s disease patients: a case series. J Clin Pharm Ther. 2014;39(5):564–6. https://doi.org/10.1111/jcpt.12179.

    Article  CAS  PubMed  Google Scholar 

  108. Benito C, Nunez E, Tolon RM, Carrier EJ, Rabano A, Hillard CJ, et al. Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer’s disease brains. J Neurosci. 2003;23(35):11136–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Ramirez BG, Blazquez C, Gomez del Pulgar T, Guzman M, de Ceballos ML. Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci. 2005;25(8):1904–13. https://doi.org/10.1523/jneurosci.4540-04.2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Solas M, Francis PT, Franco R, Ramirez MJ. CB2 receptor and amyloid pathology in frontal cortex of Alzheimer’s disease patients. Neurobiol Aging. 2013;34(3):805–8. https://doi.org/10.1016/j.neurobiolaging.2012.06.005.

    Article  CAS  PubMed  Google Scholar 

  111. Koppel J, Vingtdeux V, Marambaud P, d’Abramo C, Jimenez H, Stauber M, et al. CB2 receptor deficiency increases amyloid pathology and alters tau processing in a transgenic mouse model of Alzheimer’s disease. Mol Med. 2014;20:29–36. https://doi.org/10.2119/molmed.2013.00140.revised.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Tolon RM, Nunez E, Pazos MR, Benito C, Castillo AI, Martinez-Orgado JA, et al. The activation of cannabinoid CB2 receptors stimulates in situ and in vitro beta-amyloid removal by human macrophages. Brain Res. 2009;1283:148–54. https://doi.org/10.1016/j.brainres.2009.05.098.

    Article  CAS  PubMed  Google Scholar 

  113. Martin-Moreno AM, Brera B, Spuch C, Carro E, Garcia-Garcia L, Delgado M, et al. Prolonged oral cannabinoid administration prevents neuroinflammation, lowers beta-amyloid levels and improves cognitive performance in Tg APP 2576 mice. J Neuroinflamm. 2012;9:8. https://doi.org/10.1186/1742-2094-9-8.

    Article  CAS  Google Scholar 

  114. Fakhfouri G, Ahmadiani A, Rahimian R, Grolla AA, Moradi F, Haeri A. WIN55212-2 attenuates amyloid-beta-induced neuroinflammation in rats through activation of cannabinoid receptors and PPAR-gamma pathway. Neuropharmacology. 2012;63(4):653–66. https://doi.org/10.1016/j.neuropharm.2012.05.013.

    Article  CAS  PubMed  Google Scholar 

  115. Wu J, Bie B, Yang H, Xu JJ, Brown DL, Naguib M. Activation of the CB2 receptor system reverses amyloid-induced memory deficiency. Neurobiol Aging. 2013;34(3):791–804. https://doi.org/10.1016/j.neurobiolaging.2012.06.011.

    Article  CAS  PubMed  Google Scholar 

  116. Aso E, Juves S, Maldonado R, Ferrer I. CB2 cannabinoid receptor agonist ameliorates Alzheimer-like phenotype in AbetaPP/PS1 mice. J Alzheimers Dis. 2013;35(4):847–58. https://doi.org/10.3233/jad-130137.

    Article  PubMed  Google Scholar 

  117. Esposito G, Scuderi C, Savani C, Steardo L Jr, De Filippis D, Cottone P, et al. Cannabidiol in vivo blunts beta-amyloid induced neuroinflammation by suppressing IL-1beta and iNOS expression. Br J Pharmacol. 2007;151(8):1272–9. https://doi.org/10.1038/sj.bjp.0707337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Cheng D, Low JK, Logge W, Garner B, Karl T. Chronic cannabidiol treatment improves social and object recognition in double transgenic APPswe/PS1E9 mice. Psychopharmacology (Berl). 2014;231(15):3009–17. https://doi.org/10.1007/s00213-014-3478-5.

    Article  CAS  PubMed  Google Scholar 

  119. Cheng D, Spiro AS, Jenner AM, Garner B, Karl T. Long-term cannabidiol treatment prevents the development of social recognition memory deficits in Alzheimer’s disease transgenic mice. J Alzheimers Dis. 2014;42(4):1383–96. https://doi.org/10.3233/jad-140921.

    Article  CAS  PubMed  Google Scholar 

  120. Aso E, Sanchez-Pla A, Vegas-Lozano E, Maldonado R, Ferrer I. Cannabis-based medicine reduces multiple pathological processes in AbetaPP/PS1 mice. J Alzheimers Dis. 2015;43(3):977–91. https://doi.org/10.3233/jad-141014.

    Article  CAS  PubMed  Google Scholar 

  121. Glass M, Faull RL, Dragunow M. Loss of cannabinoid receptors in the substantia nigra in Huntington’s disease. Neuroscience. 1993;56(3):523–7.

    Article  CAS  PubMed  Google Scholar 

  122. Richfield EK, Herkenham M. Selective vulnerability in Huntington’s disease: preferential loss of cannabinoid receptors in lateral globus pallidus. Ann Neurol. 1994;36(4):577–84. https://doi.org/10.1002/ana.410360406.

    Article  CAS  PubMed  Google Scholar 

  123. Denovan-Wright EM, Robertson HA. Cannabinoid receptor messenger RNA levels decrease in a subset of neurons of the lateral striatum, cortex and hippocampus of transgenic Huntington’s disease mice. Neuroscience. 2000;98(4):705–13.

    Article  CAS  PubMed  Google Scholar 

  124. McCaw EA, Hu H, Gomez GT, Hebb AL, Kelly ME, Denovan-Wright EM. Structure, expression and regulation of the cannabinoid receptor gene (CB1) in Huntington’s disease transgenic mice. Eur J Biochem. 2004;271(23–24):4909–20. https://doi.org/10.1111/j.1432-1033.2004.04460.x.

    Article  CAS  PubMed  Google Scholar 

  125. Dowie MJ, Bradshaw HB, Howard ML, Nicholson LF, Faull RL, Hannan AJ, et al. Altered CB1 receptor and endocannabinoid levels precede motor symptom onset in a transgenic mouse model of Huntington’s disease. Neuroscience. 2009;163(1):456–65. https://doi.org/10.1016/j.neuroscience.2009.06.014.

    Article  CAS  PubMed  Google Scholar 

  126. Blazquez C, Chiarlone A, Sagredo O, Aguado T, Pazos MR, Resel E, et al. Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington’s disease. Brain. 2011;134(Pt 1):119–36. https://doi.org/10.1093/brain/awq278.

    Article  PubMed  Google Scholar 

  127. Palazuelos J, Aguado T, Pazos MR, Julien B, Carrasco C, Resel E, et al. Microglial CB2 cannabinoid receptors are neuroprotective in Huntington’s disease excitotoxicity. Brain. 2009;132(Pt 11):3152–64. https://doi.org/10.1093/brain/awp239.

    Article  PubMed  Google Scholar 

  128. Bisogno T, Martire A, Petrosino S, Popoli P, Di Marzo V. Symptom-related changes of endocannabinoid and palmitoylethanolamide levels in brain areas of R6/2 mice, a transgenic model of Huntington’s disease. Neurochem Int. 2008;52(1–2):307–13. https://doi.org/10.1016/j.neuint.2007.06.031.

    Article  CAS  PubMed  Google Scholar 

  129. Bari M, Battista N, Valenza M, Mastrangelo N, Malaponti M, Catanzaro G, et al. In vitro and in vivo models of Huntington’s disease show alterations in the endocannabinoid system. FEBS J. 2013;280(14):3376–88. https://doi.org/10.1111/febs.12329.

    Article  CAS  PubMed  Google Scholar 

  130. Lastres-Becker I, Bizat N, Boyer F, Hantraye P, Brouillet E, Fernandez-Ruiz J. Effects of cannabinoids in the rat model of Huntington’s disease generated by an intrastriatal injection of malonate. Neuroreport. 2003;14(6):813–6. https://doi.org/10.1097/01.wnr.0000067781.69995.1b.

    Article  CAS  PubMed  Google Scholar 

  131. Lastres-Becker I, Bizat N, Boyer F, Hantraye P, Fernandez-Ruiz J, Brouillet E. Potential involvement of cannabinoid receptors in 3-nitropropionic acid toxicity in vivo. Neuroreport. 2004;15(15):2375–9.

    Article  CAS  PubMed  Google Scholar 

  132. Sagredo O, Ramos JA, 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(4):843–51. https://doi.org/10.1111/j.1460-9568.2007.05717.x.

    Article  PubMed  Google Scholar 

  133. Maya-Lopez M, Colin-Gonzalez AL, Aguilera G, de Lima ME, Colpo-Ceolin A, Rangel-Lopez E, et al. Neuroprotective effect of WIN55,212-2 against 3-nitropropionic acid-induced toxicity in the rat brain: involvement of CB1 and NMDA receptors. Am J Transl Res. 2017;9(2):261–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Consroe P, Laguna J, Allender J, Snider S, Stern L, Sandyk R, et al. Controlled clinical trial of cannabidiol in Huntington’s disease. Pharmacol Biochem Behav. 1991;40(3):701–8.

    Article  CAS  PubMed  Google Scholar 

  135. Lopez-Sendon Moreno JL, Garcia Caldentey J, Trigo Cubillo P, Ruiz Romero C, Garcia Ribas G, Alonso Arias MA, et al. A double-blind, randomized, cross-over, placebo-controlled, pilot trial with Sativex in Huntington’s disease. J Neurol. 2016;263(7):1390–400. https://doi.org/10.1007/s00415-016-8145-9.

    Article  CAS  PubMed  Google Scholar 

  136. Curtis A, Mitchell I, Patel S, Ives N, Rickards H. A pilot study using nabilone for symptomatic treatment in Huntington’s disease. Mov Disord. 2009;24(15):2254–9. https://doi.org/10.1002/mds.22809.

    Article  PubMed  Google Scholar 

  137. Sallan SE, Zinberg NE, Frei E 3rd. Antiemetic effect of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy. N Engl J Med. 1975;293(16):795–7. https://doi.org/10.1056/nejm197510162931603.

    Article  CAS  PubMed  Google Scholar 

  138. Darmani NA. Delta(9)-tetrahydrocannabinol and synthetic cannabinoids prevent emesis produced by the cannabinoid CB(1) receptor antagonist/inverse agonist SR 141716A. Neuropsychopharmacology. 2001;24(2):198–203. https://doi.org/10.1016/s0893-133x(00)00197-4.

    Article  CAS  PubMed  Google Scholar 

  139. Darmani NA, Sim-Selley LJ, Martin BR, Janoyan JJ, Crim JL, Parekh B, et al. Antiemetic and motor-depressive actions of CP55,940: cannabinoid CB1 receptor characterization, distribution, and G-protein activation. Eur J Pharmacol. 2003;459(1):83–95.

    Article  CAS  PubMed  Google Scholar 

  140. Darmani NA. Delta-9-tetrahydrocannabinol differentially suppresses cisplatin-induced emesis and indices of motor function via cannabinoid CB(1) receptors in the least shrew. Pharmacol Biochem Behav. 2001;69(1–2):239–49.

    Article  CAS  PubMed  Google Scholar 

  141. Van Sickle MD, Oland LD, Mackie K, Davison JS, Sharkey KA. Delta9-tetrahydrocannabinol selectively acts on CB1 receptors in specific regions of dorsal vagal complex to inhibit emesis in ferrets. Am J Physiol Gastrointest Liver Physiol. 2003;285(3):G566–76. https://doi.org/10.1152/ajpgi.00113.2003.

    Article  PubMed  Google Scholar 

  142. Rock EM, Boulet N, Limebeer CL, Mechoulam R, Parker LA. Cannabinoid 2 (CB2) receptor agonism reduces lithium chloride-induced vomiting in Suncus murinus and nausea-induced conditioned gaping in rats. Eur J Pharmacol. 2016;786:94–9. https://doi.org/10.1016/j.ejphar.2016.06.001.

    Article  CAS  PubMed  Google Scholar 

  143. Kwiatkowska M, Parker LA, Burton P, Mechoulam R. A comparative analysis of the potential of cannabinoids and ondansetron to suppress cisplatin-induced emesis in the Suncus murinus (house musk shrew). Psychopharmacology (Berl). 2004;174(2):254–9. https://doi.org/10.1007/s00213-003-1739-9.

    Article  CAS  PubMed  Google Scholar 

  144. Parker LA, Kwiatkowska M, Burton P, Mechoulam R. Effect of cannabinoids on lithium-induced vomiting in the Suncus murinus (house musk shrew). Psychopharmacology (Berl). 2004;171(2):156–61. https://doi.org/10.1007/s00213-003-1571-2.

    Article  CAS  PubMed  Google Scholar 

  145. Sharkey KA, Cristino L, Oland LD, Van Sickle MD, Starowicz K, Pittman QJ, et al. Arvanil, anandamide and N-arachidonoyl-dopamine (NADA) inhibit emesis through cannabinoid CB1 and vanilloid TRPV1 receptors in the ferret. Eur J Neurosci. 2007;25(9):2773–82. https://doi.org/10.1111/j.1460-9568.2007.05521.x.

    Article  CAS  PubMed  Google Scholar 

  146. Sticht MA, Rock EM, Parker LA. 2-arachidonoylglycerol interferes with lithium-induced vomiting in the house musk shrew, Suncus murinus. Physiol Behav. 2013;120:228–32. https://doi.org/10.1016/j.physbeh.2013.08.015.

    Article  CAS  PubMed  Google Scholar 

  147. Parker LA, Limebeer CL, Rock EM, Litt DL, Kwiatkowska M, Piomelli D. The FAAH inhibitor URB-597 interferes with cisplatin- and nicotine-induced vomiting in the Suncus murinus (house musk shrew). Physiol Behav. 2009;97(1):121–4. https://doi.org/10.1016/j.physbeh.2009.02.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Parker LA, Niphakis MJ, Downey R, Limebeer CL, Rock EM, Sticht MA, et al. Effect of selective inhibition of monoacylglycerol lipase (MAGL) on acute nausea, anticipatory nausea, and vomiting in rats and Suncus murinus. Psychopharmacology (Berl). 2015;232(3):583–93. https://doi.org/10.1007/s00213-014-3696-x.

    Article  CAS  PubMed  Google Scholar 

  149. Pomeroy M, Fennelly JJ, Towers M. Prospective randomized double-blind trial of nabilone versus domperidone in the treatment of cytotoxic-induced emesis. Cancer Chemother Pharmacol. 1986;17(3):285–8.

    Article  CAS  PubMed  Google Scholar 

  150. Meiri E, Jhangiani H, Vredenburgh JJ, Barbato LM, Carter FJ, Yang HM, et al. Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting. Curr Med Res Opin. 2007;23(3):533–43. https://doi.org/10.1185/030079907x167525.

    Article  CAS  PubMed  Google Scholar 

  151. Lane M, Vogel CL, Ferguson J, Krasnow S, Saiers JL, Hamm J, et al. Dronabinol and prochlorperazine in combination for treatment of cancer chemotherapy-induced nausea and vomiting. J Pain Sympt Manag. 1991;6(6):352–9.

    Article  CAS  Google Scholar 

  152. Abrahamov A, Abrahamov A, Mechoulam R. An efficient new cannabinoid antiemetic in pediatric oncology. Life Sci. 1995;56(23–24):2097–102.

    Article  CAS  PubMed  Google Scholar 

  153. Elder JJ, Knoderer HM. Characterization of dronabinol usage in a pediatric oncology population. J Pediatr Pharmacol Ther. 2015;20(6):462–7. https://doi.org/10.5863/1551-6776-20.6.462.

    Article  PubMed  PubMed Central  Google Scholar 

  154. Polito S, MacDonald T, Romanick M, Jupp J, Wiernikowski J, Vennettilli A, et al. Safety and efficacy of nabilone for acute chemotherapy-induced vomiting prophylaxis in pediatric patients: a multicenter, retrospective review. Pediatr Blood Cancer. 2018;26:e2737. https://doi.org/10.1002/pbc.27374 (Epub ahead of print).

    Article  CAS  Google Scholar 

  155. Kleine-Brueggeney M, Greif R, Brenneisen R, Urwyler N, Stueber F, Theiler LG. Intravenous delta-9-tetrahydrocannabinol to prevent postoperative nausea and vomiting: a randomized controlled trial. Anesth Analg. 2015;121(5):1157–64. https://doi.org/10.1213/ane.0000000000000877.

    Article  CAS  PubMed  Google Scholar 

  156. Calignano A, La Rana G, Giuffrida A, Piomelli D. Control of pain initiation by endogenous cannabinoids. Nature. 1998;394(6690):277–81. https://doi.org/10.1038/28393.

    Article  CAS  PubMed  Google Scholar 

  157. Guindon J, Desroches J, Beaulieu P. The antinociceptive effects of intraplantar injections of 2-arachidonoyl glycerol are mediated by cannabinoid CB2 receptors. Br J Pharmacol. 2007;150(6):693–701. https://doi.org/10.1038/sj.bjp.0706990.

    Article  CAS  PubMed  Google Scholar 

  158. Starowicz K, Makuch W, Osikowicz M, Piscitelli F, Petrosino S, Di Marzo V, et al. Spinal anandamide produces analgesia in neuropathic rats: possible CB(1)- and TRPV1-mediated mechanisms. Neuropharmacology. 2012;62(4):1746–55. https://doi.org/10.1016/j.neuropharm.2011.11.021.

    Article  CAS  PubMed  Google Scholar 

  159. Lichtman AH, Leung D, Shelton CC, Saghatelian A, Hardouin C, Boger DL, et al. Reversible inhibitors of fatty acid amide hydrolase that promote analgesia: evidence for an unprecedented combination of potency and selectivity. J Pharmacol Exp Ther. 2004;311(2):441–8. https://doi.org/10.1124/jpet.104.069401.

    Article  CAS  PubMed  Google Scholar 

  160. Jayamanne A, Greenwood R, Mitchell VA, Aslan S, Piomelli D, Vaughan CW. Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models. Br J Pharmacol. 2006;147(3):281–8. https://doi.org/10.1038/sj.bjp.0706510.

    Article  CAS  PubMed  Google Scholar 

  161. Sagar DR, Kendall DA, Chapman V. Inhibition of fatty acid amide hydrolase produces PPAR-alpha-mediated analgesia in a rat model of inflammatory pain. Br J Pharmacol. 2008;155(8):1297–306. https://doi.org/10.1038/bjp.2008.335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Jhaveri MD, Richardson D, Robinson I, Garle MJ, Patel A, Sun Y, et al. Inhibition of fatty acid amide hydrolase and cyclooxygenase-2 increases levels of endocannabinoid related molecules and produces analgesia via peroxisome proliferator-activated receptor-alpha in a model of inflammatory pain. Neuropharmacology. 2008;55(1):85–93. https://doi.org/10.1016/j.neuropharm.2008.04.018.

    Article  CAS  PubMed  Google Scholar 

  163. Spradley JM, Guindon J, Hohmann AG. Inhibitors of monoacylglycerol lipase, fatty-acid amide hydrolase and endocannabinoid transport differentially suppress capsaicin-induced behavioral sensitization through peripheral endocannabinoid mechanisms. Pharmacol Res. 2010;62(3):249–58. https://doi.org/10.1016/j.phrs.2010.03.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Guindon J, Guijarro A, Piomelli D, Hohmann AG. Peripheral antinociceptive effects of inhibitors of monoacylglycerol lipase in a rat model of inflammatory pain. Br J Pharmacol. 2011;163(7):1464–78. https://doi.org/10.1111/j.1476-5381.2010.01192.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Chang L, Luo L, Palmer JA, Sutton S, Wilson SJ, Barbier AJ, et al. Inhibition of fatty acid amide hydrolase produces analgesia by multiple mechanisms. Br J Pharmacol. 2006;148(1):102–13. https://doi.org/10.1038/sj.bjp.0706699.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Jhaveri MD, Richardson D, Kendall DA, Barrett DA, Chapman V. Analgesic effects of fatty acid amide hydrolase inhibition in a rat model of neuropathic pain. J Neurosci. 2006;26(51):13318–27. https://doi.org/10.1523/jneurosci.3326-06.2006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Woodhams SG, Wong A, Barrett DA, Bennett AJ, Chapman V, Alexander SP. Spinal administration of the monoacylglycerol lipase inhibitor JZL184 produces robust inhibitory effects on nociceptive processing and the development of central sensitization in the rat. Br J Pharmacol. 2012;167(8):1609–19. https://doi.org/10.1111/j.1476-5381.2012.02179.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Clapper JR, Moreno-Sanz G, Russo R, Guijarro A, Vacondio F, Duranti A, et al. Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism. Nat Neurosci. 2010;13(10):1265–70. https://doi.org/10.1038/nn.2632.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Maurer M, Henn V, Dittrich A, Hofmann A. Delta-9-tetrahydrocannabinol shows antispastic and analgesic effects in a single case double-blind trial. Eur Arch Psychiatry Clin Neurosci. 1990;240(1):1–4.

    Article  CAS  PubMed  Google Scholar 

  170. Svendsen KB, Jensen TS, Bach FW. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ. 2004;329(7460):253. https://doi.org/10.1136/bmj.38149.566979.AE.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Wissel J, Haydn T, Muller J, Brenneis C, Berger T, Poewe W, et al. Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain : a double-blind placebo-controlled cross-over trial. J Neurol. 2006;253(10):1337–41. https://doi.org/10.1007/s00415-006-0218-8.

    Article  CAS  PubMed  Google Scholar 

  172. Toth C, Mawani S, Brady S, Chan C, Liu C, Mehina E, et al. An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain. Pain. 2012;153(10):2073–82. https://doi.org/10.1016/j.pain.2012.06.024.

    Article  CAS  PubMed  Google Scholar 

  173. Nurmikko TJ, Serpell MG, Hoggart B, Toomey PJ, Morlion BJ, Haines D. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain. 2007;133(1–3):210–20. https://doi.org/10.1016/j.pain.2007.08.028.

    Article  CAS  PubMed  Google Scholar 

  174. Wade DT, Robson P, House H, Makela P, Aram J. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin Rehabil. 2003;17(1):21–9. https://doi.org/10.1191/0269215503cr581oa.

    Article  PubMed  Google Scholar 

  175. Blake DR, Robson P, Ho M, Jubb RW, McCabe CS. Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology (Oxford). 2006;45(1):50–2. https://doi.org/10.1093/rheumatology/kei183.

    Article  CAS  PubMed  Google Scholar 

  176. Serpell MG, Notcutt W, Collin C. Sativex long-term use: an open-label trial in patients with spasticity due to multiple sclerosis. J Neurol. 2013;260(1):285–95. https://doi.org/10.1007/s00415-012-6634-z.

    Article  PubMed  Google Scholar 

  177. Serpell M, Ratcliffe S, Hovorka J, Schofield M, Taylor L, Lauder H, et al. A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment. Eur J Pain. 2014;18(7):999–1012. https://doi.org/10.1002/j.1532-2149.2013.00445.x.

    Article  CAS  PubMed  Google Scholar 

  178. Crowley K, de Vries ST, Moreno-Sanz G. Self-reported effectiveness and safety of Trokie® lozenges: a standardized formulation for the buccal delivery of cannabis extracts. Front Neurosci. 2018;12:564. https://doi.org/10.3389/fnins.2018.00564.

    Article  PubMed  PubMed Central  Google Scholar 

  179. Karst M, Salim K, Burstein S, Conrad I, Hoy L, Schneider U. Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA. 2003;290(13):1757–62. https://doi.org/10.1001/jama.290.13.1757.

    Article  CAS  PubMed  Google Scholar 

  180. Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology. 2007;68(7):515–21. https://doi.org/10.1212/01.wnl.0000253187.66183.9c.

    Article  CAS  PubMed  Google Scholar 

  181. Ellis RJ, Toperoff W, Vaida F, van den Brande G, Gonzales J, Gouaux B, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology. 2009;34(3):672–80. https://doi.org/10.1038/npp.2008.120.

    Article  CAS  PubMed  Google Scholar 

  182. Wilsey B, Marcotte T, Tsodikov A, Millman J, Bentley H, Gouaux B, et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain. 2008;9(6):506–21. https://doi.org/10.1016/j.jpain.2007.12.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, Donaghe H. Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain. 2013;14(2):136–48. https://doi.org/10.1016/j.jpain.2012.10.009.

    Article  CAS  PubMed  Google Scholar 

  184. Ware MA, Wang T, Shapiro S, Robinson A, Ducruet T, Huynh T, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ. 2010;182(14):E694–701. https://doi.org/10.1503/cmaj.091414.

    Article  PubMed  PubMed Central  Google Scholar 

  185. Wallace MS, Marcotte TD, Umlauf A, Gouaux B, Atkinson JH. Efficacy of inhaled cannabis on painful diabetic neuropathy. J Pain. 2015;16(7):616–27. https://doi.org/10.1016/j.jpain.2015.03.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED, Potts R, Fallon MT. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Sympt Manag. 2010;39(2):167–79. https://doi.org/10.1016/j.jpainsymman.2009.06.008.

    Article  Google Scholar 

  187. Lynch ME, Cesar-Rittenberg P, Hohmann AG. A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. J Pain Sympt Manag. 2014;47(1):166–73. https://doi.org/10.1016/j.jpainsymman.2013.02.018.

    Article  Google Scholar 

  188. Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL. Cannabinoid–opioid interaction in chronic pain. Clin Pharmacol Ther. 2011;90(6):844–51. https://doi.org/10.1038/clpt.2011.188.

    Article  CAS  PubMed  Google Scholar 

  189. Narang S, Gibson D, Wasan AD, Ross EL, Michna E, Nedeljkovic SS, et al. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. J Pain. 2008;9(3):254–64. https://doi.org/10.1016/j.jpain.2007.10.018.

    Article  CAS  PubMed  Google Scholar 

  190. Turcotte D, Doupe M, Torabi M, Gomori A, Ethans K, Esfahani F, et al. Nabilone as an adjunctive to gabapentin for multiple sclerosis-induced neuropathic pain: a randomized controlled trial. Pain Med. 2015;16(1):149–59. https://doi.org/10.1111/pme.12569.

    Article  PubMed  Google Scholar 

  191. Huggins JP, Smart TS, Langman S, Taylor L, Young T. An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee. Pain. 2012;153(9):1837–46. https://doi.org/10.1016/j.pain.2012.04.020.

    Article  CAS  PubMed  Google Scholar 

  192. Zhang L, Li XX, Hu XZ. Post-traumatic stress disorder risk and brain-derived neurotrophic factor Val66Met. World J Psychiatry. 2016;6(1):1–6. https://doi.org/10.5498/wjp.v6.i1.1.

    Article  PubMed  PubMed Central  Google Scholar 

  193. Burstein O, Shoshan N, Doron R, Akirav I. Cannabinoids prevent depressive-like symptoms and alterations in BDNF expression in a rat model of PTSD. Prog Neuropsychopharmacol Biol Psychiatry. 2018;84(Pt A):129–39. https://doi.org/10.1016/j.pnpbp.2018.01.026.

    Article  CAS  PubMed  Google Scholar 

  194. Ghasemi M, Abrari K, Goudarzi I, Rashidy-Pour A. Effect of WIN55-212-2 and consequences of extinction training on conditioned fear memory in PTSD male rats. Basic Clin Neurosci. 2017;8(6):493–502. https://doi.org/10.29252/nirp.bcn.8.6.493.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Fidelman S, Mizrachi Zer-Aviv T, Lange R, Hillard CJ, Akirav I. Chronic treatment with URB597 ameliorates post-stress symptoms in a rat model of PTSD. Eur Neuropsychopharmacol. 2018;28(5):630–42. https://doi.org/10.1016/j.euroneuro.2018.02.004.

    Article  CAS  PubMed  Google Scholar 

  196. Stern CA, Gazarini L, Vanvossen AC, Zuardi AW, Galve-Roperh I, Guimaraes FS, et al. Delta9-tetrahydrocannabinol alone and combined with cannabidiol mitigate fear memory through reconsolidation disruption. Eur Neuropsychopharmacol. 2015;25(6):958–65. https://doi.org/10.1016/j.euroneuro.2015.02.001.

    Article  CAS  PubMed  Google Scholar 

  197. Mizrachi Zer-Aviv T, Segev A, Akirav I. Cannabinoids and post-traumatic stress disorder: clinical and preclinical evidence for treatment and prevention. Behav Pharmacol. 2016;27(7):561–9. https://doi.org/10.1097/fbp.0000000000000253.

    Article  CAS  PubMed  Google Scholar 

  198. Hill MN, Campolongo P, Yehuda R, Patel S. Integrating endocannabinoid signaling and cannabinoids into the biology and treatment of posttraumatic stress disorder. Neuropsychopharmacology. 2018;43(1):80–102. https://doi.org/10.1038/npp.2017.162.

    Article  PubMed  Google Scholar 

  199. Fraser GA. The use of a synthetic cannabinoid in the management of treatment-resistant nightmares in posttraumatic stress disorder (PTSD). CNS Neurosci Ther. 2009;15(1):84–8. https://doi.org/10.1111/j.1755-5949.2008.00071.x.

    Article  PubMed  PubMed Central  Google Scholar 

  200. Jetly R, Heber A, Fraser G, Boisvert D. The efficacy of nabilone, a synthetic cannabinoid, in the treatment of PTSD-associated nightmares: a preliminary randomized, double-blind, placebo-controlled cross-over design study. Psychoneuroendocrinology. 2015;51:585–8. https://doi.org/10.1016/j.psyneuen.2014.11.002.

    Article  CAS  PubMed  Google Scholar 

  201. Sandyk R, Awerbuch G. Marijuana and Tourette’s syndrome. J Clin Psychopharmacol. 1988;8(6):444–5.

    Article  CAS  PubMed  Google Scholar 

  202. Hemming M, Yellowlees PM. Effective treatment of Tourette’s syndrome with marijuana. J Pychopharmacol (Oxford, England). 1993;7(4):389–91. https://doi.org/10.1177/026988119300700411.

    Article  CAS  Google Scholar 

  203. Hasan A, Rothenberger A, Munchau A, Wobrock T, Falkai P, Roessner V. Oral delta 9-tetrahydrocannabinol improved refractory Gilles de la Tourette syndrome in an adolescent by increasing intracortical inhibition: a case report. J Clin Psychopharmacol. 2010;30(2):190–2. https://doi.org/10.1097/JCP.0b013e3181d236ec.

    Article  PubMed  Google Scholar 

  204. Muller-Vahl KR, Schneider U, Koblenz A, Jobges M, Kolbe H, Daldrup T, et al. Treatment of Tourette’s syndrome with delta 9-tetrahydrocannabinol (THC): a randomized crossover trial. Pharmacopsychiatry. 2002;35(2):57–61. https://doi.org/10.1055/s-2002-25028.

    Article  CAS  PubMed  Google Scholar 

  205. Trainor D, Evans L, Bird R. Severe motor and vocal tics controlled with Sativex®. Australas Psychiatry. 2016;24(6):541–4. https://doi.org/10.1177/1039856216663737.

    Article  PubMed  Google Scholar 

  206. Zuardi AW, Cosme RA, Graeff FG, Guimaraes FS. Effects of ipsapirone and cannabidiol on human experimental anxiety. J Psychopharmacol. 1993;7(1 Suppl.):82–8. https://doi.org/10.1177/026988119300700112.

    Article  CAS  PubMed  Google Scholar 

  207. Bergamaschi MM, Queiroz RH, Chagas MH, de Oliveira DC, De Martinis BS, Kapczinski F, et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive social phobia patients. Neuropsychopharmacology. 2011;36(6):1219–26. https://doi.org/10.1038/npp.2011.6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Crippa JA, Derenusson GN, Ferrari TB, Wichert-Ana L, Duran FL, Martin-Santos R, et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol. 2011;25(1):121–30. https://doi.org/10.1177/0269881110379283.

    Article  CAS  PubMed  Google Scholar 

  209. Fusar-Poli P, Crippa JA, Bhattacharyya S, Borgwardt SJ, Allen P, Martin-Santos R, et al. Distinct effects of {delta}9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Arch Gen Psychiatry. 2009;66(1):95–105. https://doi.org/10.1001/archgenpsychiatry.2008.519.

    Article  CAS  PubMed  Google Scholar 

  210. Fraguas-Sanchez AI, Martin-Sabroso C, Torres-Suarez AI. Insights into the effects of the endocannabinoid system in cancer: a review. Br J Pharmacol. 2018;175(13):2566–80. https://doi.org/10.1111/bph.14331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Guzman M. Cannabinoids: potential anticancer agents. Nat Rev Cancer. 2003;3(10):745–55. https://doi.org/10.1038/nrc1188.

    Article  CAS  PubMed  Google Scholar 

  212. Wu X, Han L, Zhang X, Li L, Jiang C, Qiu Y, et al. Alteration of endocannabinoid system in human gliomas. J Neurochem. 2012;120(5):842–9. https://doi.org/10.1111/j.1471-4159.2011.07625.x.

    Article  CAS  PubMed  Google Scholar 

  213. Sredni ST, Huang CC, Suzuki M, Pundy T, Chou P, Tomita T. Spontaneous involution of pediatric low-grade gliomas: high expression of cannabinoid receptor 1 (CNR1) at the time of diagnosis may indicate involvement of the endocannabinoid system. Childs Nerv Syst. 2016;32(11):2061–7. https://doi.org/10.1007/s00381-016-3243-7.

    Article  PubMed  Google Scholar 

  214. Sanchez C, de Ceballos ML, Gomez del Pulgar T, Rueda D, Corbacho C, Velasco G, et al. Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res. 2001;61(15):5784–9.

    CAS  PubMed  Google Scholar 

  215. Ellert-Miklaszewska A, Grajkowska W, Gabrusiewicz K, Kaminska B, Konarska L. Distinctive pattern of cannabinoid receptor type II (CB2) expression in adult and pediatric brain tumors. Brain Res. 2007;1137(1):161–9. https://doi.org/10.1016/j.brainres.2006.12.060.

    Article  CAS  PubMed  Google Scholar 

  216. Schley M, Stander S, Kerner J, Vajkoczy P, Schupfer G, Dusch M, et al. Predominant CB2 receptor expression in endothelial cells of glioblastoma in humans. Brain Res Bull. 2009;79(5):333–7. https://doi.org/10.1016/j.brainresbull.2009.01.011.

    Article  CAS  PubMed  Google Scholar 

  217. Maccarrone M, Attina M, Cartoni A, Bari M, Finazzi-Agro A. Gas chromatography–mass spectrometry analysis of endogenous cannabinoids in healthy and tumoral human brain and human cells in culture. J Neurochem. 2001;76(2):594–601.

    Article  CAS  PubMed  Google Scholar 

  218. Petersen G, Moesgaard B, Schmid PC, Schmid HH, Broholm H, Kosteljanetz M, et al. Endocannabinoid metabolism in human glioblastomas and meningiomas compared to human non-tumour brain tissue. J Neurochem. 2005;93(2):299–309. https://doi.org/10.1111/j.1471-4159.2005.03013.x.

    Article  CAS  PubMed  Google Scholar 

  219. Contassot E, Wilmotte R, Tenan M, Belkouch MC, Schnuriger V, de Tribolet N, et al. Arachidonylethanolamide induces apoptosis of human glioma cells through vanilloid receptor-1. J Neuropathol Exp Neurol. 2004;63(9):956–63.

    Article  CAS  PubMed  Google Scholar 

  220. Hinz B, Ramer R, Eichele K, Weinzierl U, Brune K. Up-regulation of cyclooxygenase-2 expression is involved in R(+)-methanandamide-induced apoptotic death of human neuroglioma cells. Mol Pharmacol. 2004;66(6):1643–51. https://doi.org/10.1124/mol.104.002618.

    Article  CAS  PubMed  Google Scholar 

  221. Bari M, Battista N, Fezza F, Finazzi-Agro A, Maccarrone M. Lipid rafts control signaling of type-1 cannabinoid receptors in neuronal cells. Implications for anandamide-induced apoptosis. J Biol Chem. 2005;280(13):12212–20. https://doi.org/10.1074/jbc.M411642200.

    Article  CAS  PubMed  Google Scholar 

  222. Ma C, Wu TT, Jiang PC, Li ZQ, Chen XJ, Fu K, et al. Anti-carcinogenic activity of anandamide on human glioma in vitro and in vivo. Mol Med Rep. 2016;13(2):1558–62. https://doi.org/10.3892/mmr.2015.4721.

    Article  CAS  PubMed  Google Scholar 

  223. Hohmann T, Grabiec U, Ghadban C, Feese K, Dehghani F. The influence of biomechanical properties and cannabinoids on tumor invasion. Cell Adh Migr. 2017;11(1):54–67. https://doi.org/10.1080/19336918.2016.1183867.

    Article  CAS  PubMed  Google Scholar 

  224. Fowler CJ, Jonsson KO, Andersson A, Juntunen J, Jarvinen T, Vandevoorde S, et al. Inhibition of C6 glioma cell proliferation by anandamide, 1-arachidonoylglycerol, and by a water soluble phosphate ester of anandamide: variability in response and involvement of arachidonic acid. Biochem Pharmacol. 2003;66(5):757–67.

    Article  CAS  PubMed  Google Scholar 

  225. Jacobsson SO, Wallin T, Fowler CJ. Inhibition of rat C6 glioma cell proliferation by endogenous and synthetic cannabinoids: relative involvement of cannabinoid and vanilloid receptors. J Pharmacol Exp Ther. 2001;299(3):951–9.

    CAS  PubMed  Google Scholar 

  226. Massi P, Vaccani A, Ceruti S, Colombo A, Abbracchio MP, Parolaro D. Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines. J Pharmacol Exp Ther. 2004;308(3):838–45. https://doi.org/10.1124/jpet.103.061002.

    Article  CAS  PubMed  Google Scholar 

  227. Marcu JP, Christian RT, Lau D, Zielinski AJ, Horowitz MP, Lee J, et al. Cannabidiol enhances the inhibitory effects of delta9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival. Mol Cancer Ther. 2010;9(1):180–9. https://doi.org/10.1158/1535-7163.mct-09-0407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Caffarel MM, Andradas C, Mira E, Perez-Gomez E, Cerutti C, Moreno-Bueno G, et al. Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition. Mol Cancer. 2010;9:196. https://doi.org/10.1186/1476-4598-9-196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Perez-Gomez E, Andradas C, Blasco-Benito S, Caffarel MM, Garcia-Taboada E, Villa-Morales M, et al. Role of cannabinoid receptor CB2 in HER2 pro-oncogenic signaling in breast cancer. J Natl Cancer Inst. 2015;107(6):dvj077. https://doi.org/10.1093/jnci/djv077.

    Article  CAS  Google Scholar 

  230. Bisogno T, Katayama K, Melck D, Ueda N, De Petrocellis L, Yamamoto S, et al. Biosynthesis and degradation of bioactive fatty acid amides in human breast cancer and rat pheochromocytoma cells: implications for cell proliferation and differentiation. Eur J Biochem. 1998;254(3):634–42.

    Article  CAS  PubMed  Google Scholar 

  231. Melck D, De Petrocellis L, Orlando P, Bisogno T, Laezza C, Bifulco M, et al. Suppression of nerve growth factor Trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation. Endocrinology. 2000;141(1):118–26. https://doi.org/10.1210/endo.141.1.7239.

    Article  CAS  PubMed  Google Scholar 

  232. Ligresti A, Moriello AS, Starowicz K, Matias I, Pisanti S, De Petrocellis L, et al. Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther. 2006;318(3):1375–87. https://doi.org/10.1124/jpet.106.105247.

    Article  CAS  PubMed  Google Scholar 

  233. Qamri Z, Preet A, Nasser MW, Bass CE, Leone G, Barsky SH, et al. Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer. Mol Cancer Ther. 2009;8(11):3117–29. https://doi.org/10.1158/1535-7163.mct-09-0448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Grimaldi C, Pisanti S, Laezza C, Malfitano AM, Santoro A, Vitale M, et al. Anandamide inhibits adhesion and migration of breast cancer cells. Exp Cell Res. 2006;312(4):363–73. https://doi.org/10.1016/j.yexcr.2005.10.024.

    Article  CAS  PubMed  Google Scholar 

  235. Blasco-Benito S, Seijo-Vila M, Caro-Villalobos M, Tundidor I, Andradas C, Garcia-Taboada E, et al. Appraising the “entourage effect”: antitumor action of a pure cannabinoid versus a botanical drug preparation in preclinical models of breast cancer. Biochem Pharmacol. 2018. https://doi.org/10.1016/j.bcp.2018.06.025 (Epub ahead of print).

    Article  PubMed  Google Scholar 

  236. Sarfaraz S, Afaq F, Adhami VM, Mukhtar H. Cannabinoid receptor as a novel target for the treatment of prostate cancer. Cancer Res. 2005;65(5):1635–41. https://doi.org/10.1158/0008-5472.can-04-3410.

    Article  CAS  PubMed  Google Scholar 

  237. Orellana-Serradell O, Poblete CE, Sanchez C, Castellon EA, Gallegos I, Huidobro C, et al. Proapoptotic effect of endocannabinoids in prostate cancer cells. Oncol Rep. 2015;33(4):1599–608. https://doi.org/10.3892/or.2015.3746.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Chung SC, Hammarsten P, Josefsson A, Stattin P, Granfors T, Egevad L, et al. A high cannabinoid CB(1) receptor immunoreactivity is associated with disease severity and outcome in prostate cancer. Eur J Cancer. 2009;45(1):174–82. https://doi.org/10.1016/j.ejca.2008.10.010.

    Article  CAS  PubMed  Google Scholar 

  239. Cipriano M, Haggstrom J, Hammarsten P, Fowler CJ. Association between cannabinoid CB(1) receptor expression and Akt signalling in prostate cancer. PLoS One. 2013;8(6):e65798. https://doi.org/10.1371/journal.pone.0065798.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Mimeault M, Pommery N, Wattez N, Bailly C, Henichart JP. Anti-proliferative and apoptotic effects of anandamide in human prostatic cancer cell lines: implication of epidermal growth factor receptor down-regulation and ceramide production. Prostate. 2003;56(1):1–12. https://doi.org/10.1002/pros.10190.

    Article  CAS  PubMed  Google Scholar 

  241. Nithipatikom K, Isbell MA, Endsley MP, Woodliff JE, Campbell WB. Anti-proliferative effect of a putative endocannabinoid, 2-arachidonylglyceryl ether in prostate carcinoma cells. Prostaglandins Other Lipid Mediat. 2011;94(1–2):34–43. https://doi.org/10.1016/j.prostaglandins.2010.12.002.

    Article  CAS  PubMed  Google Scholar 

  242. Endsley MP, Aggarwal N, Isbell MA, Wheelock CE, Hammock BD, Falck JR, et al. Diverse roles of 2-arachidonoylglycerol in invasion of prostate carcinoma cells: location, hydrolysis and 12-lipoxygenase metabolism. Int J Cancer. 2007;121(5):984–91. https://doi.org/10.1002/ijc.22761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Nithipatikom K, Endsley MP, Isbell MA, Falck JR, Iwamoto Y, Hillard CJ, et al. 2-arachidonoylglycerol: a novel inhibitor of androgen-independent prostate cancer cell invasion. Cancer Res. 2004;64(24):8826–30. https://doi.org/10.1158/0008-5472.can-04-3136.

    Article  CAS  PubMed  Google Scholar 

  244. Nomura DK, Lombardi DP, Chang JW, Niessen S, Ward AM, Long JZ, et al. Monoacylglycerol lipase exerts dual control over endocannabinoid and fatty acid pathways to support prostate cancer. Chem Biol. 2011;18(7):846–56. https://doi.org/10.1016/j.chembiol.2011.05.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Cipriano M, Gouveia-Figueira S, Persson E, Nording M, Fowler CJ. The influence of monoacylglycerol lipase inhibition upon the expression of epidermal growth factor receptor in human PC-3 prostate cancer cells. BMC Res Notes. 2014;7:441. https://doi.org/10.1186/1756-0500-7-441.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Ramer R, Bublitz K, Freimuth N, Merkord J, Rohde H, Haustein M, et al. Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1. FASEB J. 2012;26(4):1535–48. https://doi.org/10.1096/fj.11-198184.

    Article  CAS  PubMed  Google Scholar 

  247. Suk KT, Mederacke I, Gwak GY, Cho SW, Adeyemi A, Friedman R, et al. Opposite roles of cannabinoid receptors 1 and 2 in hepatocarcinogenesis. Gut. 2016;65(10):1721–32. https://doi.org/10.1136/gutjnl-2015-310212.

    Article  CAS  PubMed  Google Scholar 

  248. Xu X, Liu Y, Huang S, Liu G, Xie C, Zhou J, et al. Overexpression of cannabinoid receptors CB1 and CB2 correlates with improved prognosis of patients with hepatocellular carcinoma. Cancer Genet Cytogenet. 2006;171(1):31–8. https://doi.org/10.1016/j.cancergencyto.2006.06.014.

    Article  CAS  PubMed  Google Scholar 

  249. DeMorrow S, Glaser S, Francis H, Venter J, Vaculin B, Vaculin S, et al. Opposing actions of endocannabinoids on cholangiocarcinoma growth: recruitment of Fas and Fas ligand to lipid rafts. J Biol Chem. 2007;282(17):13098–113. https://doi.org/10.1074/jbc.M608238200.

    Article  CAS  PubMed  Google Scholar 

  250. DeMorrow S, Francis H, Gaudio E, Venter J, Franchitto A, Kopriva S, et al. The endocannabinoid anandamide inhibits cholangiocarcinoma growth via activation of the noncanonical Wnt signaling pathway. Am J Physiol Gastrointest Liver Physiol. 2008;295(6):G1150–8. https://doi.org/10.1152/ajpgi.90455.2008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Giuliano M, Pellerito O, Portanova P, Calvaruso G, Santulli A, De Blasio A, et al. Apoptosis induced in HepG2 cells by the synthetic cannabinoid WIN: involvement of the transcription factor PPARgamma. Biochimie. 2009;91(4):457–65. https://doi.org/10.1016/j.biochi.2008.11.003.

    Article  CAS  PubMed  Google Scholar 

  252. Vara D, Salazar M, Olea-Herrero N, Guzman M, Velasco G, Diaz-Laviada I. Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy. Cell Death Differ. 2011;18(7):1099–111. https://doi.org/10.1038/cdd.2011.32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Xu D, Wang J, Zhou Z, He Z, Zhao Q. Cannabinoid WIN55, 212-2 induces cell cycle arrest and inhibits the proliferation and migration of human BEL7402 hepatocellular carcinoma cells. Mol Med Rep. 2015;12(6):7963–70. https://doi.org/10.3892/mmr.2015.4477.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Pourkhalili N, Ghahremani MH, Farsandaj N, Tavajohi S, Majdzadeh M, Parsa M, et al. Evaluation of anti-invasion effect of cannabinoids on human hepatocarcinoma cells. Toxicol Mech Methods. 2013;23(2):120–6. https://doi.org/10.3109/15376516.2012.730559.

    Article  CAS  PubMed  Google Scholar 

  255. Guzman M, Duarte MJ, Blazquez C, Ravina J, Rosa MC, Galve-Roperh I, et al. A pilot clinical study of delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. Br J Cancer. 2006;95(2):197–203. https://doi.org/10.1038/sj.bjc.6603236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Zogopoulos P, Korkolopoulou P, Patsouris E, Theocharis S. The antitumor action of cannabinoids on glioma tumorigenesis. Histol Histopathol. 2015;30(6):629–45. https://doi.org/10.14670/hh-30.629.

    Article  CAS  PubMed  Google Scholar 

  257. Ramer R, Hinz B. Antitumorigenic targets of cannabinoids: current status and implications. Expert Opin Ther Targets. 2016;20(10):1219–35. https://doi.org/10.1080/14728222.2016.1177512.

    Article  CAS  PubMed  Google Scholar 

  258. Basavarajappa BS, Cooper TB, Hungund BL. Chronic ethanol administration down-regulates cannabinoid receptors in mouse brain synaptic plasma membrane. Brain Res. 1998;793(1–2):212–8.

    Article  CAS  PubMed  Google Scholar 

  259. Thanos PK, Dimitrakakis ES, Rice O, Gifford A, Volkow ND. Ethanol self-administration and ethanol conditioned place preference are reduced in mice lacking cannabinoid CB1 receptors. Behav Brain Res. 2005;164(2):206–13. https://doi.org/10.1016/j.bbr.2005.06.021.

    Article  CAS  PubMed  Google Scholar 

  260. Serrano A, Rivera P, Pavon FJ, Decara J, Suarez J, Rodriguez de Fonseca F, et al. Differential effects of single versus repeated alcohol withdrawal on the expression of endocannabinoid system-related genes in the rat amygdala. Alcohol Clin Exp Res. 2012;36(6):984–94. https://doi.org/10.1111/j.1530-0277.2011.01686.x.

    Article  CAS  PubMed  Google Scholar 

  261. Gallate JE, Mallet PE, McGregor IS. Combined low dose treatment with opioid and cannabinoid receptor antagonists synergistically reduces the motivation to consume alcohol in rats. Psychopharmacology (Berl). 2004;173(1–2):210–6. https://doi.org/10.1007/s00213-003-1694-5.

    Article  CAS  PubMed  Google Scholar 

  262. Mitrirattanakul S, Lopez-Valdes HE, Liang J, Matsuka Y, Mackie K, Faull KF, et al. Bidirectional alterations of hippocampal cannabinoid 1 receptors and their endogenous ligands in a rat model of alcohol withdrawal and dependence. Alcohol Clin Exp Res. 2007;31(5):855–67. https://doi.org/10.1111/j.1530-0277.2007.00366.x.

    Article  CAS  PubMed  Google Scholar 

  263. Femenia T, Garcia-Gutierrez MS, Manzanares J. CB1 receptor blockade decreases ethanol intake and associated neurochemical changes in fawn-hooded rats. Alcohol Clin Exp Res. 2010;34(1):131–41. https://doi.org/10.1111/j.1530-0277.2009.01074.x.

    Article  CAS  PubMed  Google Scholar 

  264. Rubio M, Villain H, Docagne F, Roussel BD, Ramos JA, Vivien D, et al. Pharmacological activation/inhibition of the cannabinoid system affects alcohol withdrawal-induced neuronal hypersensitivity to excitotoxic insults. PLoS One. 2011;6(8):e23690. https://doi.org/10.1371/journal.pone.0023690.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Hungund BL, Basavarajappa BS. Distinct differences in the cannabinoid receptor binding in the brain of C57BL/6 and DBA/2 mice, selected for their differences in voluntary ethanol consumption. J Neurosci Res. 2000;60(1):122–8.

    Article  CAS  PubMed  Google Scholar 

  266. Cippitelli A, Bilbao A, Gorriti MA, Navarro M, Massi M, Piomelli D, et al. The anandamide transport inhibitor AM404 reduces ethanol self-administration. Eur J Neurosci. 2007;26(2):476–86. https://doi.org/10.1111/j.1460-9568.2007.05665.x.

    Article  PubMed  Google Scholar 

  267. Poncelet M, Maruani J, Calassi R, Soubrie P. Overeating, alcohol and sucrose consumption decrease in CB1 receptor deleted mice. Neurosci Lett. 2003;343(3):216–8.

    Article  CAS  PubMed  Google Scholar 

  268. Wang L, Liu J, Harvey-White J, Zimmer A, Kunos G. Endocannabinoid signaling via cannabinoid receptor 1 is involved in ethanol preference and its age-dependent decline in mice. Proc Natl Acad Sci USA. 2003;100(3):1393–8. https://doi.org/10.1073/pnas.0336351100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Lallemand F, de Witte P. Ethanol induces higher BEC in CB1 cannabinoid receptor knockout mice while decreasing ethanol preference. Alcohol Alcohol. 2005;40(1):54–62. https://doi.org/10.1093/alcalc/agh115.

    Article  CAS  PubMed  Google Scholar 

  270. Vinod KY, Yalamanchili R, Thanos PK, Vadasz C, Cooper TB, Volkow ND, et al. Genetic and pharmacological manipulations of the CB(1) receptor alter ethanol preference and dependence in ethanol preferring and nonpreferring mice. Synapse. 2008;62(8):574–81. https://doi.org/10.1002/syn.20533.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. Vinod KY, Sanguino E, Yalamanchili R, Manzanares J, Hungund BL. Manipulation of fatty acid amide hydrolase functional activity alters sensitivity and dependence to ethanol. J Neurochem. 2008;104(1):233–43. https://doi.org/10.1111/j.1471-4159.2007.04956.x.

    Article  CAS  PubMed  Google Scholar 

  272. Ortega-Álvaro A, Ternianov A, Aracil-Fernandez A, Navarrete F, Garcia-Gutierrez MS, Manzanares J. Role of cannabinoid CB2 receptor in the reinforcing actions of ethanol. Addict Biol. 2015;20(1):43–55. https://doi.org/10.1111/adb.12076.

    Article  CAS  PubMed  Google Scholar 

  273. Ferrer B, Bermudez-Silva FJ, Bilbao A, Alvarez-Jaimes L, Sanchez-Vera I, Giuffrida A, et al. Regulation of brain anandamide by acute administration of ethanol. Biochem J. 2007;404(1):97–104. https://doi.org/10.1042/bj20061898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Rubio M, McHugh D, Fernandez-Ruiz J, Bradshaw H, Walker JM. Short-term exposure to alcohol in rats affects brain levels of anandamide, other N-acylethanolamines and 2-arachidonoyl-glycerol. Neurosci Lett. 2007;421(3):270–4. https://doi.org/10.1016/j.neulet.2007.05.052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. Gonzalez S, Cascio MG, Fernandez-Ruiz J, Fezza F, Di Marzo V, Ramos JA. Changes in endocannabinoid contents in the brain of rats chronically exposed to nicotine, ethanol or cocaine. Brain Res. 2002;954(1):73–81.

    Article  CAS  PubMed  Google Scholar 

  276. Vinod KY, Yalamanchili R, Xie S, Cooper TB, Hungund BL. Effect of chronic ethanol exposure and its withdrawal on the endocannabinoid system. Neurochem Int. 2006;49(6):619–25. https://doi.org/10.1016/j.neuint.2006.05.002.

    Article  CAS  PubMed  Google Scholar 

  277. Colombo G, Serra S, Brunetti G, Gomez R, Melis S, Vacca G, et al. Stimulation of voluntary ethanol intake by cannabinoid receptor agonists in ethanol-preferring sP rats. Psychopharmacology (Berl). 2002;159(2):181–7. https://doi.org/10.1007/s002130100887.

    Article  CAS  PubMed  Google Scholar 

  278. Alen F, Santos A, Moreno-Sanz G, Gonzalez-Cuevas G, Gine E, Franco-Ruiz L, et al. Cannabinoid-induced increase in relapse-like drinking is prevented by the blockade of the glycine-binding site of N-methyl-d-aspartate receptors. Neuroscience. 2009;158(2):465–73. https://doi.org/10.1016/j.neuroscience.2008.10.002.

    Article  CAS  PubMed  Google Scholar 

  279. Klugmann M, Klippenstein V, Leweke FM, Spanagel R, Schneider M. Cannabinoid exposure in pubertal rats increases spontaneous ethanol consumption and NMDA receptor associated protein levels. Int J Neuropsychopharmacol. 2011;14(4):505–17. https://doi.org/10.1017/s1461145710001562.

    Article  CAS  PubMed  Google Scholar 

  280. Lopez-Moreno JA, Gonzalez-Cuevas G, Rodriguez de Fonseca F, Navarro M. Long-lasting increase of alcohol relapse by the cannabinoid receptor agonist WIN 55,212-2 during alcohol deprivation. J Neurosci. 2004;24(38):8245–52. https://doi.org/10.1523/jneurosci.2179-04.2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  281. Hamelink C, Hampson A, Wink DA, Eiden LE, Eskay RL. Comparison of cannabidiol, antioxidants, and diuretics in reversing binge ethanol-induced neurotoxicity. J Pharmacol Exp Ther. 2005;314(2):780–8. https://doi.org/10.1124/jpet.105.085779.

    Article  CAS  PubMed  Google Scholar 

  282. Liput DJ, Hammell DC, Stinchcomb AL, Nixon K. Transdermal delivery of cannabidiol attenuates binge alcohol-induced neurodegeneration in a rodent model of an alcohol use disorder. Pharmacol Biochem Behav. 2013;111:120–7. https://doi.org/10.1016/j.pbb.2013.08.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  283. Soyka M, Koller G, Schmidt P, Lesch OM, Leweke M, Fehr C, et al. Cannabinoid receptor 1 blocker rimonabant (SR 141716) for treatment of alcohol dependence: results from a placebo-controlled, double-blind trial. J Clin Psychopharmacol. 2008;28(3):317–24. https://doi.org/10.1097/JCP.0b013e318172b8bc.

    Article  CAS  PubMed  Google Scholar 

  284. Weerts EM, Kim YK, Wand GS, Dannals RF, Lee JS, Frost JJ, et al. Differences in delta- and mu-opioid receptor blockade measured by positron emission tomography in naltrexone-treated recently abstinent alcohol-dependent subjects. Neuropsychopharmacology. 2008;33(3):653–65. https://doi.org/10.1038/sj.npp.1301440.

    Article  CAS  PubMed  Google Scholar 

  285. George DT, Herion DW, Jones CL, Phillips MJ, Hersh J, Hill D, et al. Rimonabant (SR141716) has no effect on alcohol self-administration or endocrine measures in nontreatment-seeking heavy alcohol drinkers. Psychopharmacology (Berl). 2010;208(1):37–44. https://doi.org/10.1007/s00213-009-1704-3.

    Article  CAS  PubMed  Google Scholar 

  286. Metrik J, Spillane NS, Leventhal AM, Kahler CW. Marijuana use and tobacco smoking cessation among heavy alcohol drinkers. Drug Alcohol Depend. 2011;119(3):194–200. https://doi.org/10.1016/j.drugalcdep.2011.06.004.

    Article  PubMed  PubMed Central  Google Scholar 

  287. Solinas M, Panlilio LV, Tanda G, Makriyannis A, Matthews SA, Goldberg SR. Cannabinoid agonists but not inhibitors of endogenous cannabinoid transport or metabolism enhance the reinforcing efficacy of heroin in rats. Neuropsychopharmacology. 2005;30(11):2046–57. https://doi.org/10.1038/sj.npp.1300754.

    Article  CAS  PubMed  Google Scholar 

  288. Li JX, Koek W, France CP. Interactions between delta(9)-tetrahydrocannabinol and heroin: self-administration in rhesus monkeys. Behav Pharmacol. 2012;23(8):754–61. https://doi.org/10.1097/FBP.0b013e32835a3907.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  289. Maguire DR, France CP. Effects of daily delta-9-tetrahydrocannabinol treatment on heroin self-administration in rhesus monkeys. Behav Pharmacol. 2016;27(2-3 Spec Issue):249–57. https://doi.org/10.1097/fbp.0000000000000192.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  290. Karimi S, Azizi P, Shamsizadeh A, Haghparast A. Role of intra-accumbal cannabinoid CB1 receptors in the potentiation, acquisition and expression of morphine-induced conditioned place preference. Behav Brain Res. 2013;247:125–31. https://doi.org/10.1016/j.bbr.2013.03.022.

    Article  CAS  PubMed  Google Scholar 

  291. Khaleghzadeh-Ahangar H, Haghparast A. Intra-accumbal CB1 receptor blockade reduced extinction and reinstatement of morphine. Physiol Behav. 2015;149:212–9. https://doi.org/10.1016/j.physbeh.2015.06.005.

    Article  CAS  PubMed  Google Scholar 

  292. Fattore L, Spano S, Cossu G, Deiana S, Fadda P, Fratta W. Cannabinoid CB(1) antagonist SR 141716A attenuates reinstatement of heroin self-administration in heroin-abstinent rats. Neuropharmacology. 2005;48(8):1097–104. https://doi.org/10.1016/j.neuropharm.2005.01.022.

    Article  CAS  PubMed  Google Scholar 

  293. Katsidoni V, Anagnostou I, Panagis G. Cannabidiol inhibits the reward-facilitating effect of morphine: involvement of 5-HT1A receptors in the dorsal raphe nucleus. Addict Biol. 2013;18(2):286–96. https://doi.org/10.1111/j.1369-1600.2012.00483.x.

    Article  CAS  PubMed  Google Scholar 

  294. Wilkerson JL, Ghosh S, Mustafa M, Abdullah RA, Niphakis MJ, Cabrera R, et al. The endocannabinoid hydrolysis inhibitor SA-57: Intrinsic antinociceptive effects, augmented morphine-induced antinociception, and attenuated heroin seeking behavior in mice. Neuropharmacology. 2017;114:156–67. https://doi.org/10.1016/j.neuropharm.2016.11.015.

    Article  CAS  PubMed  Google Scholar 

  295. Stopponi S, Soverchia L, Ubaldi M, Cippitelli A, Serpelloni G, Ciccocioppo R. Chronic THC during adolescence increases the vulnerability to stress-induced relapse to heroin seeking in adult rats. Eur Neuropsychopharmacol. 2014;24(7):1037–45. https://doi.org/10.1016/j.euroneuro.2013.12.012.

    Article  CAS  PubMed  Google Scholar 

  296. Prilutskaya M, Bersani FS, Corazza O, Molchanov S. Impact of synthetic cannabinoids on the duration of opioid-related withdrawal and craving among patients of addiction clinics in Kazakhstan: a prospective case-control study. Hum Psychopharmacol. 2017. https://doi.org/10.1002/hup.2618 (Epub 2017 Jun 20).

    Article  PubMed  Google Scholar 

  297. Merritt JC, Crawford WJ, Alexander PC, Anduze AL, Gelbart SS. Effect of marihuana on intraocular and blood pressure in glaucoma. Ophthalmology. 1980;87(3):222–8.

    Article  CAS  PubMed  Google Scholar 

  298. Porcella A, Maxia C, Gessa GL, Pani L. The synthetic cannabinoid WIN55212-2 decreases the intraocular pressure in human glaucoma resistant to conventional therapies. Eur J Neurosci. 2001;13(2):409–12.

    Article  CAS  PubMed  Google Scholar 

  299. Chien FY, Wang RF, Mittag TW, Podos SM. Effect of WIN 55212-2, a cannabinoid receptor agonist, on aqueous humor dynamics in monkeys. Arch Ophthalmol. 2003;121(1):87–90.

    Article  CAS  PubMed  Google Scholar 

  300. Song ZH, Slowey CA. Involvement of cannabinoid receptors in the intraocular pressure-lowering effects of WIN55212-2. J Pharmacol Exp Ther. 2000;292(1):136–9.

    CAS  PubMed  Google Scholar 

  301. Szczesniak AM, Maor Y, Robertson H, Hung O, Kelly ME. Nonpsychotropic cannabinoids, abnormal cannabidiol and canabigerol-dimethyl heptyl, act at novel cannabinoid receptors to reduce intraocular pressure. J Ocul Pharmacol Ther. 2011;27(5):427–35. https://doi.org/10.1089/jop.2011.0041.

    Article  CAS  PubMed  Google Scholar 

  302. Merritt JC, Perry DD, Russell DN, Jones BF. Topical delta 9-tetrahydrocannabinol and aqueous dynamics in glaucoma. J Clin Pharmacol. 1981;21(8–9 Suppl.):467s–71s.

    Article  CAS  PubMed  Google Scholar 

  303. Crandall J, Matragoon S, Khalifa YM, Borlongan C, Tsai NT, Caldwell RB, et al. Neuroprotective and intraocular pressure-lowering effects of (-)delta9-tetrahydrocannabinol in a rat model of glaucoma. Ophthalmic Res. 2007;39(2):69–75. https://doi.org/10.1159/000099240.

    Article  CAS  PubMed  Google Scholar 

  304. El-Remessy AB, Khalil IE, Matragoon S, Abou-Mohamed G, Tsai NJ, Roon P, et al. Neuroprotective effect of (-)delta9-tetrahydrocannabinol and cannabidiol in N-methyl-d-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite. Am J Pathol. 2003;163(5):1997–2008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  305. Pinar-Sueiro S, Zorrilla Hurtado JA, Veiga-Crespo P, Sharma SC, Vecino E. Neuroprotective effects of topical CB1 agonist WIN 55212-2 on retinal ganglion cells after acute rise in intraocular pressure induced ischemia in rat. Exp Eye Res. 2013;110:55–8. https://doi.org/10.1016/j.exer.2013.02.009.

    Article  CAS  PubMed  Google Scholar 

  306. Slusar JE, Cairns EA, Szczesniak AM, Bradshaw HB, Di Polo A, Kelly ME. The fatty acid amide hydrolase inhibitor, URB597, promotes retinal ganglion cell neuroprotection in a rat model of optic nerve axotomy. Neuropharmacology. 2013;72:116–25. https://doi.org/10.1016/j.neuropharm.2013.04.018.

    Article  CAS  PubMed  Google Scholar 

  307. Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015;313(24):2456–73. https://doi.org/10.1001/jama.2015.6358.

    Article  CAS  PubMed  Google Scholar 

  308. Danovitch I, Gorelick DA. State of the art treatments for cannabis dependence. Psychiatr Clin N Am. 2012;35(2):309–26. https://doi.org/10.1016/j.psc.2012.03.003.

    Article  Google Scholar 

  309. Bonnet U, Preuss UW. The cannabis withdrawal syndrome: current insights. Subst Abuse Rehabil. 2017;8:9–37. https://doi.org/10.2147/sar.s109576.

    Article  PubMed  PubMed Central  Google Scholar 

  310. Soyka M, Preuss U, Hoch E. Cannabis-induced disorders. Nervenarzt. 2017;88(3):311–25. https://doi.org/10.1007/s00115-017-0281-7.

    Article  CAS  PubMed  Google Scholar 

  311. Wright S, Metts J. Recreational cannabinoid use: the hazards behind the “high”. J Fam Pract. 2016;65(11):770–9.

    PubMed  Google Scholar 

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Correspondence to Ana Isabel Torres-Suárez.

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Ana Isabel Fraguas-Sánchez was granted a research fellowship (FPU14/06441) from the Spanish Ministry of Education. Ana Isabel Fraguas-Sánchez and Ana Isabel Torres-Suárez have no conflicts of interest that are directly relevant to the contents of this article.

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Fraguas-Sánchez, A.I., Torres-Suárez, A.I. Medical Use of Cannabinoids. Drugs 78, 1665–1703 (2018). https://doi.org/10.1007/s40265-018-0996-1

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