1. Rudd RA, Aleshire N, Zibbell JE, Gladden RM. Increases in drug and opioid overdose deaths—United States, 2000–2014. MMWR Morb Mortal Wkly Rep. 2016;64(50–51):1378–82.

2. Drug Overdose Deaths | Drug Overdose | CDC Injury Center [Internet]; 2018. https://www.cdc.gov/drugoverdose/data/statedeaths.html. Cited 17 May 2019.

3. Jordan CJ, Cao J, Newman AH, Xi Z-X. Progress in agonist therapy for substance use disorders: lessons learned from methadone and buprenorphine. Neuropharmacology. 2019. https://doi.org/10.1016/j.neuropharm.2019.04.015.

4. Jordan CJ, Xi Z-X. Discovery and development of varenicline for smoking cessation. Expert Opin Drug Discov. 2018;13(7):671–83.

5. Xi Z-X, Gardner EL. Hypothesis-driven medication discovery for the treatment of psychostimulant addiction. Curr Drug Abuse Rev. 2008;1(3):303–27.

6. Kalivas PW, Volkow ND. New medications for drug addiction hiding in glutamatergic neuroplasticity. Mol Psychiatry. 2011;16(10):974–86.

7. Filip M, Frankowska M, Sadakierska-Chudy A, Suder A, Szumiec L, Mierzejewski P, et al. GABAB receptors as a therapeutic strategy in substance use disorders: focus on positive allosteric modulators. Neuropharmacology. 2015;88:36–47.

8. Volkow ND, Jones EB, Einstein EB, Wargo EM. Prevention and treatment of opioid misuse and addiction: a review. JAMA Psychiatry. 2019;76(2):208–16.

9. Volkow ND, Wise RA, Baler R. The dopamine motive system: implications for drug and food addiction. Nat Rev Neurosci. 2017;18(12):741–52.

10. Ostroumov A, Dani JA. Inhibitory plasticity of mesocorticolimbic circuits in addiction and mental illness. Trends Neurosci. 2018;41(12):898–910.

11. Koob GF, Volkow ND. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry. 2016;3(8):760–73.

12. Parsons LH, Hurd YL. Endocannabinoid signalling in reward and addiction. Nat Rev Neurosci. 2015;16(10):579–94.

13. Trigo JM, Le Foll B. Inhibition of monoacylglycerol lipase (MAGL) enhances cue-induced reinstatement of nicotine-seeking behavior in mice. Psychopharmacology (Berl). 2016;233(10):1815–22.

14. Serrano A, Parsons LH. Endocannabinoid influence in drug reinforcement, dependence and addiction-related behaviors. Pharmacol Ther. 2011;132(3):215–41.

15. Ligresti A, Cascio MG, Di Marzo V. Endocannabinoid metabolic pathways and enzymes. Curr Drug Targets CNS Neurol Disord. 2005;4(6):615–23.

16. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258(5090):1946–9.

17. McPartland JM, Glass M, Pertwee RG. Meta-analysis of cannabinoid ligand binding affinity and receptor distribution: interspecies differences. Br J Pharmacol. 2007;152(5):583–93.

18. Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58(3):389–462.

19. Sugiura T, Waku K. 2-Arachidonoylglycerol and the cannabinoid receptors. Chem Phys Lipids. 2000;108(1–2):89–106.

20. Long JZ, Li W, Booker L, Burston JJ, Kinsey SG, Schlosburg JE, et al. Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat Chem Biol. 2009;5(1):37–44.

21. Kaczocha M, Glaser ST, Deutsch DG. Identification of intracellular carriers for the endocannabinoid anandamide. Proc Natl Acad Sci USA. 2009;106(15):6375–80.

22. Oddi S, Fezza F, Pasquariello N, D’Agostino A, Catanzaro G, De Simone C, et al. Molecular identification of albumin and Hsp70 as cytosolic anandamide-binding proteins. Chem Biol. 2009;16(6):624–32.

23. Hermann A, Kaczocha M, Deutsch DG. 2-Arachidonoylglycerol (2-AG) membrane transport: history and outlook. AAPS J. 2006;8(2):E409–12.

24. Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci USA. 1990;87(5):1932–6.

25. Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci. 2003;4(11):873–84.

26. Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M. Endocannabinoid-mediated control of synaptic transmission. Physiol Rev. 2009;89(1):309–80.

27. Castillo PE, Younts TJ, Chávez AE, Hashimotodani Y. Endocannabinoid signaling and synaptic function. Neuron. 2012;76(1):70–81.

28. Howlett AC, Blume LC, Dalton GD. CB(1) cannabinoid receptors and their associated proteins. Curr Med Chem. 2010;17(14):1382–93.

29. Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev. 2003;83(3):1017–66.

30. Stella N. Cannabinoid and cannabinoid-like receptors in microglia, astrocytes, and astrocytomas. Glia. 2010;58(9):1017–30.

31. Han J, Kesner P, Metna-Laurent M, Duan T, Xu L, Georges F, et al. Acute cannabinoids impair working memory through astroglial CB1 receptor modulation of hippocampal LTD. Cell. 2012;148(5):1039–50.

32. Oliveira da Cruz JF, Robin LM, Drago F, Marsicano G, Metna-Laurent M. Astroglial type-1 cannabinoid receptor (CB1): a new player in the tripartite synapse. Neuroscience. 2016;26(323):35–42.

33. Navarrete M, Araque A. Endocannabinoids mediate neuron-astrocyte communication. Neuron. 2008;57(6):883–93.

34. Mothet JP, Parent AT, Wolosker H, Brady RO, Linden DJ, Ferris CD, et al. D-serine is an endogenous ligand for the glycine site of the N-methyl-d-aspartate receptor. Proc Natl Acad Sci USA. 2000;97(9):4926–31.

35. Metna-Laurent M, Marsicano G. Rising stars: modulation of brain functions by astroglial type-1 cannabinoid receptors. Glia. 2015;63(3):353–64.

36. Robin LM, Oliveira da Cruz JF, Langlais VC, Martin-Fernandez M, Metna-Laurent M, Busquets-Garcia A, et al. Astroglial CB1 receptors determine synaptic D-serine availability to enable recognition memory. Neuron. 2018;98(5):935–944.e5.

37. Calabrese EJ, Rubio-Casillas A. Biphasic effects of THC in memory and cognition. Eur J Clin Investig. 2018;48(5):e12920.

38. Mailleux P, Vanderhaeghen JJ. Distribution of neuronal cannabinoid receptor in the adult rat brain: a comparative receptor binding radioautography and in situ hybridization histochemistry. Neuroscience. 1992;48(3):655–68.

39. Mátyás F, Yanovsky Y, Mackie K, Kelsch W, Misgeld U, Freund TF. Subcellular localization of type 1 cannabinoid receptors in the rat basal ganglia. Neuroscience. 2006;137(1):337–61.

40. Han X, He Y, Bi G-H, Zhang H-Y, Song R, Liu Q-R, et al. CB1 receptor activation on VgluT2-expressing glutamatergic neurons underlies Δ9-tetrahydrocannabinol (Δ9-THC)-induced aversive effects in mice. Sci Rep. 2017;7(1):12315.

41. Mackie K. Distribution of cannabinoid receptors in the central and peripheral nervous system. Handb Exp Pharmacol. 2005;168:299–325.

42. Fratta W, Fattore L. Molecular mechanisms of cannabinoid addiction. Curr Opin Neurobiol. 2013;23(4):487–92.

43. Gueudet C, Santucci V, Rinaldi-Carmona M, Soubrié P, Le Fur G. The CB1 cannabinoid receptor antagonist SR 141716A affects A9 dopamine neuronal activity in the rat. Neuroreport. 1995;6(10):1421–5.

44. De Luca MA, Bimpisidis Z, Melis M, Marti M, Caboni P, Valentini V, et al. Stimulation of in vivo dopamine transmission and intravenous self-administration in rats and mice by JWH-018, a Spice cannabinoid. Neuropharmacology. 2015;99:705–14.

45. De Luca MA, Castelli MP, Loi B, Porcu A, Martorelli M, Miliano C, et al. Native CB1 receptor affinity, intrinsic activity and accumbens shell dopamine stimulant properties of third generation SPICE/K2 cannabinoids: BB-22, 5F-PB-22, 5F-AKB-48 and STS-135. Neuropharmacology. 2016;105:630–8.

46. Mateo Y, Johnson KA, Covey DP, Atwood BK, Wang H-L, Zhang S, et al. Endocannabinoid actions on cortical terminals orchestrate local modulation of dopamine release in the nucleus accumbens. Neuron. 2017;96(5):1112–1126.e5.

47. French ED, Dillon K, Wu X. Cannabinoids excite dopamine neurons in the ventral tegmentum and substantia nigra. Neuroreport. 1997;8(3):649–52.

48. Braida D, Iosuè S, Pegorini S, Sala M. Delta9-tetrahydrocannabinol-induced conditioned place preference and intracerebroventricular self-administration in rats. Eur J Pharmacol. 2004;506(1):63–9.

49. Gardner EL. Endocannabinoid signaling system and brain reward: emphasis on dopamine. Pharmacol Biochem Behav. 2005;81(2):263–84.

50. Spiller KJ, Bi G-H, He Y, Galaj E, Gardner EL, Xi Z-X. Cannabinoid CB1 and CB2 receptor mechanisms underlie cannabis reward and aversion in rats. Br J Pharmacol. 2019;176(9):1268–81.

51. Takahashi RN, Singer G. Self-administration of delta 9-tetrahydrocannabinol by rats. Pharmacol Biochem Behav. 1979;11(6):737–40.

52. Fattore L, Cossu G, Martellotta CM, Fratta W. Intravenous self-administration of the cannabinoid CB1 receptor agonist WIN 55,212-2 in rats. Psychopharmacology (Berl). 2001;156(4):410–6.

53. Lefever TW, Marusich JA, Antonazzo KR, Wiley JL. Evaluation of WIN 55,212-2 self-administration in rats as a potential cannabinoid abuse liability model. Pharmacol Biochem Behav. 2014;118:30–5.

54. Spencer S, Neuhofer D, Chioma VC, Garcia-Keller C, Schwartz DJ, Allen N, et al. A model of Δ9-tetrahydrocannabinol self-administration and reinstatement that alters synaptic plasticity in nucleus accumbens. Biol Psychiatry. 2018;84(8):601–10.

55. Szabo B, Siemes S, Wallmichrath I. Inhibition of GABAergic neurotransmission in the ventral tegmental area by cannabinoids. Eur J Neurosci. 2002;15(12):2057–61.

56. Lupica CR, Riegel AC, Hoffman AF. Marijuana and cannabinoid regulation of brain reward circuits. Br J Pharmacol. 2004;143(2):227–34.

57. Lupica CR, Riegel AC. Endocannabinoid release from midbrain dopamine neurons: a potential substrate for cannabinoid receptor antagonist treatment of addiction. Neuropharmacology. 2005;48(8):1105–16.

58. Lupica CR, Hoffman AF. Cannabinoid disruption of learning mechanisms involved in reward processing. Learn Mem. 2018;25(9):435–45.

59. Maldonado R, Valverde O, Berrendero F. Involvement of the endocannabinoid system in drug addiction. Trends Neurosci. 2006;29(4):225–32.

60. Fattore L, Fadda P, Spano MS, Pistis M, Fratta W. Neurobiological mechanisms of cannabinoid addiction. Mol Cell Endocrinol. 2008;286(1–2 Suppl 1):S97–107.

61. Raft D, Gregg J, Ghia J, Harris L. Effects of intravenous tetrahydrocannabinol on experimental and surgical pain. Psychological correlates of the analgesic response. Clin Pharmacol Ther. 1977;21(1):26–33.

62. D’Souza DC, Perry E, MacDougall L, Ammerman Y, Cooper T, Wu Y-T, et al. The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology. 2004;29(8):1558–72.

63. Gregg JM, Small EW, Moore R, Raft D, Toomey TC. Emotional response to intravenous delta9tetrahydrocannabinol during oral surgery. J Oral Surg. 1976;34(4):301–13.

64. Farris SG, Zvolensky MJ, Boden MT, Bonn-Miller MO. Cannabis use expectancies mediate the relation between depressive symptoms and cannabis use among cannabis-dependent veterans. J Addict Med. 2014;8(2):130–6.

65. Tanda G, Munzar P, Goldberg SR. Self-administration behavior is maintained by the psychoactive ingredient of marijuana in squirrel monkeys. Nat Neurosci. 2000;3(11):1073–4.

66. Justinova Z, Tanda G, Redhi GH, Goldberg SR. Self-administration of delta9-tetrahydrocannabinol (THC) by drug naive squirrel monkeys. Psychopharmacology (Berl). 2003;169(2):135–40.

67. Mansbach RS, Nicholson KL, Martin BR, Balster RL. Failure of Delta(9)-tetrahydrocannabinol and CP 55,940 to maintain intravenous self-administration under a fixed-interval schedule in rhesus monkeys. Behav Pharmacol. 1994;5(2):219–25.

68. John WS, Martin TJ, Nader MA. Behavioral determinants of cannabinoid self-administration in old world monkeys. Neuropsychopharmacology. 2017;42(7):1522–30.

69. Gardner EL, Paredes W, Smith D, Donner A, Milling C, Cohen D, et al. Facilitation of brain stimulation reward by delta 9-tetrahydrocannabinol. Psychopharmacology. 1988;96(1):142–4.

70. Lepore M, Liu X, Savage V, Matalon D, Gardner EL. Genetic differences in delta 9-tetrahydrocannabinol-induced facilitation of brain stimulation reward as measured by a rate-frequency curve-shift electrical brain stimulation paradigm in three different rat strains. Life Sci. 1996;58(25):PL365–72.

71. Katsidoni V, Kastellakis A, Panagis G. Biphasic effects of Δ9-tetrahydrocannabinol on brain stimulation reward and motor activity. Int J Neuropsychopharmacol. 2013;16(10):2273–84.

72. Vlachou S, Nomikos GG, Stephens DN, Panagis G. Lack of evidence for appetitive effects of Delta 9-tetrahydrocannabinol in the intracranial self-stimulation and conditioned place preference procedures in rodents. Behav Pharmacol. 2007;18(4):311–9.

73. Kwilasz AJ, Negus SS. Dissociable effects of the cannabinoid receptor agonists Δ9-tetrahydrocannabinol and CP55940 on pain-stimulated versus pain-depressed behavior in rats. J Pharmacol Exp Ther. 2012;343(2):389–400.

74. Negus SS, Miller LL. Intracranial self-stimulation to evaluate abuse potential of drugs. Pharmacol Rev. 2014;66(3):869–917.

75. Wiebelhaus JM, Grim TW, Owens RA, Lazenka MF, Sim-Selley LJ, Abdullah RA, et al. Δ9-tetrahydrocannabinol and endocannabinoid degradative enzyme inhibitors attenuate intracranial self-stimulation in mice. J Pharmacol Exp Ther. 2015;352(2):195–207.

76. Panagis G, Vlachou S, Nomikos GG. Behavioral pharmacology of cannabinoids with a focus on preclinical models for studying reinforcing and dependence-producing properties. Curr Drug Abuse Rev. 2008;1(3):350–74.

77. Vlachou S, Panagis G. Regulation of brain reward by the endocannabinoid system: a critical review of behavioral studies in animals. Curr Pharm Des. 2014;20(13):2072–88.

78. Castañeda E, Moss DE, Oddie SD, Whishaw IQ. THC does not affect striatal dopamine release: microdialysis in freely moving rats. Pharmacol Biochem Behav. 1991;40(3):587–91.

79. Wang H-L, Qi J, Zhang S, Wang H, Morales M. Rewarding effects of optical stimulation of ventral tegmental area glutamatergic neurons. J Neurosci. 2015;35(48):15948–54.

80. Manzanares J, Cabañero D, Puente N, García-Gutiérrez MS, Grandes P, Maldonado R. Role of the endocannabinoid system in drug addiction. Biochem Pharmacol. 2018;157:108–21.

81. Jordan CJ, Xi Z-X. Progress in brain cannabinoid CB2 receptor research: from genes to behavior. Neurosci Biobehav Rev. 2019;98:208–20.

82. Xi Z-X, Peng X-Q, Li X, Song R, Zhang H-Y, Liu Q-R, et al. Brain cannabinoid CB 2 receptors modulate cocaine’s actions in mice. Nat Neurosci. 2011;14(9):1160–6.

83. Zhang H-Y, Gao M, Liu Q-R, Bi G-H, Li X, Yang H-J, et al. Cannabinoid CB2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice. Proc Natl Acad Sci USA. 2014;111(46):E5007–15.

84. Zhang H-Y, Gao M, Shen H, Bi G-H, Yang H-J, Liu Q-R, et al. Expression of functional cannabinoid CB2 receptor in VTA dopamine neurons in rats. Addict Biol. 2017;22(3):752–65.

85. Foster DJ, Wilson JM, Remke DH, Mahmood MS, Uddin MJ, Wess J, et al. Antipsychotic-like effects of M4 positive allosteric modulators are mediated by CB2 receptor-dependent inhibition of dopamine release. Neuron. 2016;91(6):1244–52.

86. Delis F, Polissidis A, Poulia N, Justinova Z, Nomikos GG, Goldberg SR, et al. Attenuation of cocaine-induced conditioned place preference and motor activity via cannabinoid CB2 receptor agonism and CB1 receptor antagonism in rats. Int J Neuropsychopharmacol. 2017;20(3):269–78.

87. Zhang H-Y, Bi G-H, Li X, Li J, Qu H, Zhang S-J, et al. Species differences in cannabinoid receptor 2 and receptor responses to cocaine self-administration in mice and rats. Neuropsychopharmacology. 2015;40(4):1037–51.

88. Aracil-Fernández A, Trigo JM, García-Gutiérrez MS, Ortega-Álvaro A, Ternianov A, Navarro D, et al. Decreased cocaine motor sensitization and self-administration in mice overexpressing cannabinoid CB 2 receptors. Neuropsychopharmacology. 2012;37(7):1749–63.

89. Gamaleddin I, Zvonok A, Makriyannis A, Goldberg SR, Le Foll B. Effects of a selective cannabinoid CB2 agonist and antagonist on intravenous nicotine self administration and reinstatement of nicotine seeking. PLoS One. 2012;7(1):e29900.

90. Solinas M, Panlilio LV, Goldberg SR. Exposure to delta-9-tetrahydrocannabinol (THC) increases subsequent heroin taking but not heroin’s reinforcing efficacy: a self-administration study in rats. Neuropsychopharmacology. 2004;29(7):1301–11.

91. 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.

92. Linsenbardt DN, Boehm SL. Agonism of the endocannabinoid system modulates binge-like alcohol intake in male C57BL/6J mice: involvement of the posterior ventral tegmental area. Neuroscience. 2009;164(2):424–34.

93. Caillé S, Alvarez-Jaimes L, Polis I, Stouffer DG, Parsons LH. Specific alterations of extracellular endocannabinoid levels in the nucleus accumbens by ethanol, heroin, and cocaine self-administration. J Neurosci. 2007;27(14):3695–702.

94. Wang H, Treadway T, Covey DP, Cheer JF, Lupica CR. Cocaine-induced endocannabinoid mobilization in the ventral tegmental area. Cell Rep. 2015;12(12):1997–2008.

95. Le Foll B, Gorelick DA, Goldberg SR. The future of endocannabinoid-oriented clinical research after CB1 antagonists. Psychopharmacology. 2009;205(1):171–4.

96. Maccioni P, Colombo G, Carai MAM. Blockade of the cannabinoid CB1 receptor and alcohol dependence: preclinical evidence and preliminary clinical data. CNS Neurol Disord Drug Targets. 2010;9(1):55–9.

97. Gamaleddin IH, Trigo JM, Gueye AB, Zvonok A, Makriyannis A, Goldberg SR, et al. Role of the endogenous cannabinoid system in nicotine addiction: novel insights. Front Psychiatry. 2015;6:41.

98. Stern CAJ, de Carvalho CR, Bertoglio LJ, Takahashi RN. Effects of cannabinoid drugs on aversive or rewarding drug-associated memory extinction and reconsolidation. Neuroscience. 2018;01(370):62–80.

99. Rinaldi-Carmona M, Barth F, Héaulme M, Shire D, Calandra B, Congy C, et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett. 1994;350(2–3):240–4.

100. Mato S, Pazos A, Valdizán EM. Cannabinoid receptor antagonism and inverse agonism in response to SR141716A on cAMP production in human and rat brain. Eur J Pharmacol. 2002;443(1–3):43–6.

101. Le Foll B, Goldberg SR. Cannabinoid CB1 receptor antagonists as promising new medications for drug dependence. J Pharmacol Exp Ther. 2005;312(3):875–83.

102. Wiskerke J, Pattij T, Schoffelmeer ANM, De Vries TJ. The role of CB1 receptors in psychostimulant addiction. Addict Biol. 2008;13(2):225–38.

103. Cahill K, Ussher MH. Cannabinoid type 1 receptor antagonists for smoking cessation. Cochrane Database Syst Rev. 2011;3:CD005353.

104. Gaal LFV, Rissanen AM, Scheen AJ, Ziegler O, Rössner S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet. 2005;365(9468):1389–97.

105. Elrashidi MY, Ebbert JO. Emerging drugs for the treatment of tobacco dependence: 2014 update. Expert Opin Emerg Drugs. 2014;19(2):243–60.

106. Sloan ME, Gowin JL, Ramchandani VA, Hurd YL, Le Foll B. The endocannabinoid system as a target for addiction treatment: trials and tribulations. Neuropharmacology. 2017;15(124):73–83.

107. Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup AV. A meta-analysis of the efficacy and safety of the anti-obesity agent Rimonabant. Ugeskr Laeg. 2007;169(50):4360–3.

108. Sam AH, Salem V, Ghatei MA. Rimonabant: from RIO to ban. J Obes. 2011;2011:432607.

109. Morgan CJA, Das RK, Joye A, Curran HV, Kamboj SK. Cannabidiol reduces cigarette consumption in tobacco smokers: preliminary findings. Addict Behav. 2013;38(9):2433–6.

110. Chorvat RJ. Peripherally restricted CB1 receptor blockers. Bioorg Med Chem Lett. 2013;23(17):4751–60.

111. Cluny NL, Vemuri VK, Chambers AP, Limebeer CL, Bedard H, Wood JT, et al. A novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduces food intake and body weight, but does not cause malaise, in rodents. Br J Pharmacol. 2010;161(3):629–42.

112. Kunos G, Tam J. The case for peripheral CB 1 receptor blockade in the treatment of visceral obesity and its cardiometabolic complications. Br J Pharmacol. 2011;163(7):1423–31.

113. Chorvat RJ, Berbaum J, Seriacki K, McElroy JF. JD-5006 and JD-5037: peripherally restricted (PR) cannabinoid-1 receptor blockers related to SLV-319 (Ibipinabant) as metabolic disorder therapeutics devoid of CNS liabilities. Bioorg Med Chem Lett. 2012;22(19):6173–80.

114. Tam J, Cinar R, Liu J, Godlewski G, Wesley D, Jourdan T, et al. Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell Metab. 2012;16(2):167–79.

115. Tai S, Nikas SP, Shukla VG, Vemuri K, Makriyannis A, Järbe TUC. Cannabinoid withdrawal in mice: inverse agonist vs neutral antagonist. Psychopharmacology (Berl). 2015;232(15):2751–61.

116. Godlewski G, Cinar R, Coffey NJ, Liu J, Jourdan T, Mukhopadhyay B, et al. Targeting peripheral CB1 receptors reduces ethanol intake via a gut–brain axis. Cell Metab. 2019;29(6):1320–1333.e8.

117. Xi Z-X, Spiller K, Pak AC, Gilbert J, Dillon C, Li X, et al. Cannabinoid CB1 receptor antagonists attenuate cocaine’s rewarding effects: experiments with self-administration and brain-stimulation reward in rats. Neuropsychopharmacology. 2008;33(7):1735–45.

118. He X-H, Jordan CJ, Vemuri K, Bi G-H, Zhan J, Gardner EL, et al. Cannabinoid CB1 receptor neutral antagonist AM4113 inhibits heroin self-administration without depressive side effects in rats. Acta Pharmacol Sin. 2019;40:365–73.

119. Gardner EL, Gamaleddin I, Manzanares RJ, Rodrigues FF. The endocannabinoid system: useful targets for anti-addiction treatments? Subst Abuse. 2013;34:324–5.

120. Gueye AB, Pryslawsky Y, Trigo JM, Poulia N, Delis F, Antoniou K, et al. The CB1 neutral antagonist AM4113 retains the therapeutic efficacy of the inverse agonist rimonabant for nicotine dependence and weight loss with better psychiatric tolerability. Int J Neuropsychopharmacol. 2016. https://doi.org/10.1093/ijnp/pyw068.

121. Alvarado M, Decara J, Luque MJ, Hernandez-Folgado L, Gómez-Cañas M, Gómez-Ruiz M, et al. Novel antiobesity agents: synthesis and pharmacological evaluation of analogues of Rimonabant and of LH21. Bioorg Med Chem. 2013;21(7):1708–16.

122. Seltzman HH, Maitra R, Bortoff K, Henson J, Reggio PH, Wesley D, et al. Metabolic profiling of CB1 neutral antagonists. Methods Enzymol. 2017;593:199–215.

123. Salamone JD, McLaughlin PJ, Sink K, Makriyannis A, Parker LA. Cannabinoid CB1 receptor inverse agonists and neutral antagonists: effects on food intake, food-reinforced behavior and food aversions. Physiol Behav. 2007;91(4):383–8.

124. Sink KS, McLaughlin PJ, Wood JAT, Brown C, Fan P, Vemuri VK, et al. The novel cannabinoid CB1 receptor neutral antagonist AM4113 suppresses food intake and food-reinforced behavior but does not induce signs of nausea in rats. Neuropsychopharmacology. 2008;33(4):946–55.

125. Chambers AP, Vemuri VK, Peng Y, Wood JT, Olszewska T, Pittman QJ, et al. A neutral CB1 receptor antagonist reduces weight gain in rat. Am J Physiol Regul Integr Comp Physiol. 2007;293(6):R2185–93.

126. Järbe TUC, LeMay BJ, Olszewska T, Vemuri VK, Wood JT, Makriyannis A. Intrinsic effects of AM4113, a putative neutral CB1 receptor selective antagonist, on open-field behaviors in rats. Pharmacol Biochem Behav. 2008;91(1):84–90.

127. Balla A, Dong B, Shilpa BM, Vemuri K, Makriyannis A, Pandey SC, et al. Cannabinoid-1 receptor neutral antagonist reduces binge-like alcohol consumption and alcohol-induced accumbal dopaminergic signaling. Neuropharmacology. 2018;15(131):200–8.

128. Schindler CW, Redhi GH, Vemuri K, Makriyannis A, Le Foll B, Bergman J, et al. Blockade of nicotine and cannabinoid reinforcement and relapse by a cannabinoid CB1-receptor neutral antagonist AM4113 and inverse agonist rimonabant in squirrel monkeys. Neuropsychopharmacology. 2016;41(9):2283–93.

129. Kangas BD, Delatte MS, Vemuri VK, Thakur GA, Nikas SP, Subramanian KV, et al. Cannabinoid discrimination and antagonism by CB(1) neutral and inverse agonist antagonists. J Pharmacol Exp Ther. 2013;344(3):561–7.

130. Wills KL, Vemuri K, Kalmar A, Lee A, Limebeer CL, Makriyannis A, et al. CB1 antagonism: interference with affective properties of acute naloxone-precipitated morphine withdrawal in rats. Psychopharmacology (Berl). 2014;231(22):4291–300.

131. Jagerovic N, Hernandez-Folgado L, Alkorta I, Goya P, Navarro M, Serrano A, et al. Discovery of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1h-1,2,4-triazole, a novel in vivo cannabinoid antagonist containing a 1,2,4-triazole motif. J Med Chem. 2004;47(11):2939–42.

132. Chen RZ, Frassetto A, Lao JZ, Huang R-RC, Xiao JC, Clements MJ, et al. Pharmacological evaluation of LH-21, a newly discovered molecule that binds to cannabinoid CB1 receptor. Eur J Pharmacol. 2008;584(2–3):338–42.

133. Pavon FJ, Bilbao A, Hernández-Folgado L, Cippitelli A, Jagerovic N, Abellán G, et al. Antiobesity effects of the novel in vivo neutral cannabinoid receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole–LH 21. Neuropharmacology. 2006;51(2):358–66.

134. Pavón FJ, Serrano A, Pérez-Valero V, Jagerovic N, Hernández-Folgado L, Bermúdez-Silva FJ, et al. Central versus peripheral antagonism of cannabinoid CB1 receptor in obesity: effects of LH-21, a peripherally acting neutral cannabinoid receptor antagonist, in Zucker rats. J Neuroendocrinol. 2008;20(Suppl 1):116–23.

135. Alonso M, Serrano A, Vida M, Crespillo A, Hernandez-Folgado L, Jagerovic N, et al. Anti-obesity efficacy of LH-21, a cannabinoid CB1 receptor antagonist with poor brain penetration, in diet-induced obese rats. Br J Pharmacol. 2012;165(7):2274–91.

136. Gardner EL, Bi G-H, Thakur GA, Makriyannis A, Seltzman HH, He X-Y, et al. Preclinical evaluation of neutral cannabinoid CB1 receptor antagonists and cannabinoid CB1 receptor negative allosteric modulators for treating drug addiction. Int J Neuropsychopharmacol. 2016. Report No.: Meeting Abstract-PM288.

137. Price MR, Baillie GL, Thomas A, Stevenson LA, Easson M, Goodwin R, et al. Allosteric modulation of the cannabinoid CB1 receptor. Mol Pharmacol. 2005;68(5):1484–95.

138. Jing L, Qiu Y, Zhang Y, Li J-X. Effects of the cannabinoid CB1 receptor allosteric modulator ORG 27569 on reinstatement of cocaine- and methamphetamine-seeking behavior in rats. Drug Alcohol Depend. 2014;1(143):251–6.

139. Gamage TF, Ignatowska-Jankowska BM, Wiley JL, Abdelrahman M, Trembleau L, Greig IR, et al. In-vivo pharmacological evaluation of the CB1-receptor allosteric modulator Org-27569. Behav Pharmacol. 2014;25(2):182–5.

140. Ding Y, Qiu Y, Jing L, Thorn DA, Zhang Y, Li J-X. Behavioral effects of the cannabinoid CB1 receptor allosteric modulator ORG27569 in rats. Pharmacol Res Perspect. 2014;2(6):e00069.

141. Hofer SC, Ralvenius WT, Gachet MS, Fritschy J-M, Zeilhofer HU, Gertsch J. Localization and production of peptide endocannabinoids in the rodent CNS and adrenal medulla. Neuropharmacology. 2015;98:78–89.

142. Bauer M, Chicca A, Tamborrini M, Eisen D, Lerner R, Lutz B, et al. Identification and quantification of a new family of peptide endocannabinoids (Pepcans) showing negative allosteric modulation at CB1 receptors. J Biol Chem. 2012;287(44):36944–67.

143. Petrucci V, Chicca A, Glasmacher S, Paloczi J, Cao Z, Pacher P, et al. Pepcan-12 (RVD-hemopressin) is a CB2 receptor positive allosteric modulator constitutively secreted by adrenals and in liver upon tissue damage. Sci Rep. 2017;7(1):9560.

144. Gomes I, Grushko JS, Golebiewska U, Hoogendoorn S, Gupta A, Heimann AS, et al. Novel endogenous peptide agonists of cannabinoid receptors. FASEB J. 2009;23(9):3020–9.

145. Ferrante C, Recinella L, Leone S, Chiavaroli A, Di Nisio C, Martinotti S, et al. Anorexigenic effects induced by RVD-hemopressin(α) administration. Pharmacol Rep. 2017;69(6):1402–7.

146. Leone S, Recinella L, Chiavaroli A, Martinotti S, Ferrante C, Mollica A, et al. Emotional disorders induced by Hemopressin and RVD-hemopressin(α) administration in rats. Pharmacol Rep. 2017;69(6):1247–53.

147. Atwood BK, Mackie K. CB2: a cannabinoid receptor with an identity crisis. Br J Pharmacol. 2010;160(3):467–79.

148. Lanciego JL, Barroso-Chinea P, Rico AJ, Conte-Perales L, Callén L, Roda E, et al. Expression of the mRNA coding the cannabinoid receptor 2 in the pallidal complex of Macaca fascicularis. J Psychopharmacol (Oxford). 2011;25(1):97–104.

149. Sierra S, Luquin N, Rico AJ, Gómez-Bautista V, Roda E, Dopeso-Reyes IG, et al. Detection of cannabinoid receptors CB1 and CB2 within basal ganglia output neurons in macaques: changes following experimental parkinsonism. Brain Struct Funct. 2015;220(5):2721–38.

150. Ignatowska-Jankowska BM, Muldoon PP, Lichtman AH, Damaj MI. The cannabinoid CB2 receptor is necessary for nicotine-conditioned place preference, but not other behavioral effects of nicotine in mice. Psychopharmacology (Berl). 2013;229(4):591–601.

151. Navarrete F, Rodríguez-Arias M, Martín-García E, Navarro D, García-Gutiérrez MS, Aguilar MA, et al. Role of CB2 cannabinoid receptors in the rewarding, reinforcing, and physical effects of nicotine. Neuropsychopharmacology. 2013;38(12):2515–24.

152. Liu Q-R, Canseco-Alba A, Zhang H-Y, Tagliaferro P, Chung M, Dennis E, et al. Cannabinoid type 2 receptors in dopamine neurons inhibits psychomotor behaviors, alters anxiety, depression and alcohol preference. Sci Rep. 2017;7(1):17410.

153. Ortega-Álvaro A, Ternianov A, Aracil-Fernández A, Navarrete F, García-Gutiérrez MS, Manzanares J. Role of cannabinoid CB2 receptor in the reinforcing actions of ethanol. Addict Biol. 2015;20(1):43–55.

154. Powers MS, Breit KR, Chester JA. Genetic versus pharmacological assessment of the role of cannabinoid type 2 receptors in alcohol reward-related behaviors. Alcohol Clin Exp Res. 2015;39(12):2438–46.

155. Bystrowska B, Frankowska M, Smaga I, Pomierny-Chamioło L, Filip M. effects of cocaine self-administration and its extinction on the rat brain cannabinoid CB1 and CB2 receptors. Neurotox Res. 2018;34:547–58.

156. Bystrowska B, Frankowska M, Smaga I, Niedzielska-Andres E, Pomierny-Chamioło L, Filip M. cocaine-induced reinstatement of cocaine seeking provokes changes in the endocannabinoid and N-acylethanolamine levels in rat brain structures. Molecules. 2019;24(6):E1125.

157. Huffman JW. CB2 receptor ligands. Mini Rev Med Chem. 2005;5(7):641–9.

158. Ma Z, Gao F, Larsen B, Gao M, Luo Z, Chen D, et al. Mechanisms of cannabinoid CB2 receptor-mediated reduction of dopamine neuronal excitability in mouse ventral tegmental area. EBioMedicine. 2019;42:225–37.

159. Canseco-Alba A, Schanz N, Sanabria B, Zhao J, Lin Z, Liu Q-R, et al. Behavioral effects of psychostimulants in mutant mice with cell-type specific deletion of CB2 cannabinoid receptors in dopamine neurons. Behav Brain Res. 2018;30(360):286–97.

160. Valenzano KJ, Tafesse L, Lee G, Harrison JE, Boulet JM, Gottshall SL, et al. Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology. 2005;48(5):658–72.

161. Adamczyk P, Miszkiel J, McCreary AC, Filip M, Papp M, Przegaliński E. The effects of cannabinoid CB1, CB2 and vanilloid TRPV1 receptor antagonists on cocaine addictive behavior in rats. Brain Res. 2012;20(1444):45–54.

162. Wiley JL, Beletskaya ID, Ng EW, Dai Z, Crocker PJ, Mahadevan A, et al. Resorcinol derivatives: a novel template for the development of cannabinoid CB(1)/CB(2) and CB(2)-selective agonists. J Pharmacol Exp Ther. 2002;301(2):679–89.

163. Alavi MS, Hosseinzadeh H, Shamsizadeh A, Roohbakhsh A. The effect of O-1602, an atypical cannabinoid, on morphine-induced conditioned place preference and physical dependence. Pharmacol Rep. 2016;68(3):592–7.

164. Zhang M, Dong L, Zou H, Li J, Li Q, Wang G, et al. Effects of cannabinoid type 2 receptor agonist AM1241 on morphine-induced antinociception, acute and chronic tolerance, and dependence in mice. J Pain. 2018;19(10):1113–29.

165. Li A-L, Lin X, Dhopeshwarkar AS, Thomaz AC, Carey LM, Liu Y, et al. Cannabinoid CB2 agonist AM1710 differentially suppresses distinct pathological pain states and attenuates morphine tolerance and withdrawal. Mol Pharmacol. 2019;95(2):155–68.

166. Grenald SA, Young MA, Wang Y, Ossipov MH, Ibrahim MM, Largent-Milnes TM, et al. Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists. Neuropharmacology. 2017;116:59–70.

167. Ibrahim MM, Deng H, Zvonok A, Cockayne DA, Kwan J, Mata HP, et al. Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc Natl Acad Sci USA. 2003;100(18):10529–33.

168. Yang P, Wang L, Feng R, Almehizia AA, Tong Q, Myint KZ, et al. Novel triaryl sulfonamide derivatives as selective cannabinoid receptor 2 inverse agonists and osteoclast inhibitors: discovery, optimization, and biological evaluation. J Med Chem. 2013;56:2045–58.

169. Jordan C, Feng XW, Bi G-H, Liang Y, Han X, Xie X-Q, et al. Xie2-64 is a promising cannabinoid CB2 receptor ligand that reduces cocaine abuse-related behaviors in rodents. Addict Biol. 2019. (in press).

170. Melis M, Pistis M, Perra S, Muntoni AL, Pillolla G, Gessa GL. Endocannabinoids mediate presynaptic inhibition of glutamatergic transmission in rat ventral tegmental area dopamine neurons through activation of CB1 receptors. J Neurosci. 2004;24(1):53–62.

171. Panlilio LV, Justinova Z, Goldberg SR. Inhibition of FAAH and activation of PPAR: New approaches to the treatment of cognitive dysfunction and drug addiction. Pharmacol Ther. 2013;138(1):84–102.

172. Deutsch DG. A personal retrospective: elevating anandamide (AEA) by targeting fatty acid amide hydrolase (FAAH) and the fatty acid binding proteins (FABPs). Front Pharmacol [Internet]; 2016. Cited 6 Mar 2019.

173. Alexander JP, Cravatt BF. Mechanism of carbamate inactivation of FAAH: implications for the design of covalent inhibitors and in vivo functional probes for enzymes. Chem Biol. 2005;12(11):1179–87.

174. Justinova Z, Mangieri RA, Bortolato M, Chefer SI, Mukhin AG, Clapper JR, et al. Fatty acid amide hydrolase inhibition heightens anandamide signaling without producing reinforcing effects in primates. Biol Psychiatry. 2008;64(11):930–7.

175. Adamczyk P, McCreary AC, Przegalinski E, Mierzejewski P, Bienkowski P, Filip M. The effects of fatty acid amide hydrolase inhibitors on maintenance of cocaine and food self-administration and on reinstatement of cocaine-seeking and food-taking behavior in rats. J Physiol Pharmacol. 2009;60(3):119–25.

176. Chauvet C, Nicolas C, Thiriet N, Lardeux MV, Duranti A, Solinas M. Chronic stimulation of the tone of endogenous anandamide reduces cue- and stress-induced relapse in rats. Int J Neuropsychopharmacol. 2014. https://doi.org/10.1093/ijnp/pyu025.

177. 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.

178. McCallum AL, Limebeer CL, Parker LA. Reducing endocannabinoid metabolism with the fatty acid amide hydrolase inhibitor, URB597, fails to modify reinstatement of morphine-induced conditioned floor preference and naloxone-precipitated morphine withdrawal-induced conditioned floor avoidance. Pharmacol Biochem Behav. 2010;96(4):496–500.

179. Manwell LA, Satvat E, Lang ST, Allen CP, Leri F, Parker LA. FAAH inhibitor, URB-597, promotes extinction and CB(1) antagonist, SR141716, inhibits extinction of conditioned aversion produced by naloxone-precipitated morphine withdrawal, but not extinction of conditioned preference produced by morphine in rats. Pharmacol Biochem Behav. 2009;94(1):154–62.

180. Ramesh D, Ross GR, Schlosburg JE, Owens RA, Abdullah RA, Kinsey SG, et al. Blockade of endocannabinoid hydrolytic enzymes attenuates precipitated opioid withdrawal symptoms in mice. J Pharmacol Exp Ther. 2011;339(1):173–85.

181. Shahidi S, Hasanein P. Behavioral effects of fatty acid amide hydrolase inhibition on morphine withdrawal symptoms. Brain Res Bull. 2011;86(1–2):118–22.

182. Scherma M, Panlilio LV, Fadda P, Fattore L, Gamaleddin I, Le Foll B, et al. Inhibition of anandamide hydrolysis by cyclohexyl carbamic acid 3′-carbamoyl-3-yl ester (URB597) reverses abuse-related behavioral and neurochemical effects of nicotine in rats. J Pharmacol Exp Ther. 2008;327(2):482–90.

183. Forget B, Guranda M, Gamaleddin I, Goldberg SR, Le Foll B. Attenuation of cue-induced reinstatement of nicotine seeking by URB597 through cannabinoid CB1 receptor in rats. Psychopharmacology (Berl). 2016;233(10):1823–8.

184. Forget B, Coen KM, Le Foll B. Inhibition of fatty acid amide hydrolase reduces reinstatement of nicotine seeking but not break point for nicotine self-administration—comparison with CB(1) receptor blockade. Psychopharmacology (Berl). 2009;205(4):613–24.

185. Justinova Z, Panlilio LV, Moreno-Sanz G, Redhi GH, Auber A, Secci ME, et al. Effects of fatty acid amide hydrolase (FAAH) inhibitors in non-human primate models of nicotine reward and relapse. Neuropsychopharmacology. 2015;40(9):2185–97.

186. Cippitelli A, Astarita G, Duranti A, Caprioli G, Ubaldi M, Stopponi S, et al. Endocannabinoid regulation of acute and protracted nicotine withdrawal: effect of FAAH inhibition. PLoS One. 2011;6(11):e28142.

187. Melis M, Pillolla G, Luchicchi A, Muntoni AL, Yasar S, Goldberg SR, et al. Endogenous fatty acid ethanolamides suppress nicotine-induced activation of mesolimbic dopamine neurons through nuclear receptors. J Neurosci. 2008;28(51):13985–94.

188. Luchicchi A, Lecca S, Carta S, Pillolla G, Muntoni AL, Yasar S, et al. Effects of fatty acid amide hydrolase inhibition on neuronal responses to nicotine, cocaine and morphine in the nucleus accumbens shell and ventral tegmental area: involvement of PPAR-alpha nuclear receptors. Addict Biol. 2010;15(3):277–88.

189. Blednov YA, Cravatt BF, Boehm SL, Walker D, Harris RA. Role of endocannabinoids in alcohol consumption and intoxication: studies of mice lacking fatty acid amide hydrolase. Neuropsychopharmacology. 2007;32(7):1570–82.

190. Basavarajappa BS, Yalamanchili R, Cravatt BF, Cooper TB, Hungund BL. Increased ethanol consumption and preference and decreased ethanol sensitivity in female FAAH knockout mice. Neuropharmacology. 2006;50(7):834–44.

191. Cippitelli A, Cannella N, Braconi S, Duranti A, Tontini A, Bilbao A, et al. Increase of brain endocannabinoid anandamide levels by FAAH inhibition and alcohol abuse behaviours in the rat. Psychopharmacology (Berl). 2008;198(4):449–60.

192. Zhou Y, Schwartz BI, Giza J, Gross SS, Lee FS, Kreek MJ. Blockade of alcohol escalation and “relapse” drinking by pharmacological FAAH inhibition in male and female C57BL/6J mice. Psychopharmacology (Berl). 2017;234(19):2955–70.

193. Solinas M, Justinova Z, Goldberg SR, Tanda G. Anandamide administration alone and after inhibition of fatty acid amide hydrolase (FAAH) increases dopamine levels in the nucleus accumbens shell in rats. J Neurochem. 2006;98(2):408–19.

194. Gobbi G, Bambico FR, Mangieri R, Bortolato M, Campolongo P, Solinas M, et al. Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis. Proc Natl Acad Sci USA. 2005;102(51):18620–5.

195. Wiley JL, Walentiny DM, Wright MJ, Beardsley PM, Burston JJ, Poklis JL, et al. Endocannabinoid contribution to Δ9-tetrahydrocannabinol discrimination in rodents. Eur J Pharmacol. 2014;15(737):97–105.

196. Kathuria S, Gaetani S, Fegley D, Valiño F, Duranti A, Tontini A, et al. Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med. 2003;9(1):76–81.

197. Piomelli D, Tarzia G, Duranti A, Tontini A, Mor M, Compton TR, et al. Pharmacological profile of the selective FAAH inhibitor KDS-4103 (URB597). CNS Drug Rev. 2006;12(1):21–38.

198. 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.

199. Li GL, Winter H, Arends R, Jay GW, Le V, Young T, et al. Assessment of the pharmacology and tolerability of PF-04457845, an irreversible inhibitor of fatty acid amide hydrolase-1, in healthy subjects. Br J Clin Pharmacol. 2012;73(5):706–16.

200. Pawsey S, Wood M, Browne H, Donaldson K, Christie M, Warrington S. Safety, tolerability and pharmacokinetics of FAAH inhibitor V158866: a double-blind, randomised, placebo-controlled phase i study in healthy volunteers. Drugs R D. 2016;16(2):181–91.

201. Kaur R, Sidhu P, Singh S. What failed BIA 10-2474 phase I clinical trial? Global speculations and recommendations for future Phase I trials. J Pharmacol Pharmacother. 2016;7(3):120–6.

202. Kerbrat A, Ferré J-C, Fillatre P, Ronzière T, Vannier S, Carsin-Nicol B, et al. Acute neurologic disorder from an inhibitor of fatty acid amide hydrolase. N Engl J Med. 2016;375(18):1717–25.

203. Janssen Research & Development, LLC Voluntarily Suspends Dosing in Phase 2 Clinical Trials of Experimental Treatment for Mood Disorders | Janssen [Internet]; 2016. https://web.archive.org/web/20160125052230/http://www.janssen.com/janssen-research-development-llc-voluntarily-suspends-dosing-phase-2-clinical-trials-experimental. Cited 12 May 2019.

204. FAAH inhibitor safety under microscope after Bial drug trial death [Internet]. in-pharmatechnologist.com. https://www.in-pharmatechnologist.com/Article/2016/01/19/FAAH-inhibitor-safety-under-microscope-after-Bial-drug-trial-death. Cited 12 May 2019.

205. van Esbroeck ACM, Janssen APA, Cognetta AB, Ogasawara D, Shpak G, van der Kroeg M, et al. Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474. Science. 2017;356(6342):1084–7.

206. FDA finds drugs under investigation in the U.S. related to French BIA 10-2474 drug do not pose similar safety risks. FDA [Internet]; 2018. http://www.fda.gov/drugs/drug-safety-and-availability/fda-finds-drugs-under-investigation-us-related-french-bia-10-2474-drug-do-not-pose-similar-safety. Cited 6 Aug 2019.

207. Postnov A, Schmidt ME, Pemberton DJ, de Hoon J, van Hecken A, van den Boer M, et al. Fatty acid amide hydrolase inhibition by JNJ-42165279: a multiple-ascending dose and a positron emission tomography study in healthy volunteers. Clin Transl Sci. 2018;11(4):397–404.

208. Wagenlehner FME, van Till JWO, Houbiers JGA, Martina RV, Cerneus DP, Melis JHJM, et al. Fatty acid amide hydrolase inhibitor treatment in men with chronic prostatitis/chronic pelvic pain syndrome: an adaptive double-blind, randomized controlled trial. Urology. 2017;103:191–7.

209. D’Souza DC, Cortes-Briones J, Creatura G, Bluez G, Thurnauer H, Deaso E, et al. Efficacy and safety of a fatty acid amide hydrolase inhibitor (PF-04457845) in the treatment of cannabis withdrawal and dependence in men: a double-blind, placebo-controlled, parallel group, phase 2a single-site randomised controlled trial. Lancet Psychiatry. 2019;6(1):35–45.

210. Dinh TP, Kathuria S, Piomelli D. RNA interference suggests a primary role for monoacylglycerol lipase in the degradation of the endocannabinoid 2-arachidonoylglycerol. Mol Pharmacol. 2004;66(5):1260–4.

211. Long JZ, Nomura DK, Cravatt BF. Characterization of monoacylglycerol lipase inhibition reveals differences in central and peripheral endocannabinoid metabolism. Chem Biol. 2009;16(7):744–53.

212. Long JZ, Nomura DK, Vann RE, Walentiny DM, Booker L, Jin X, et al. Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo. Proc Natl Acad Sci USA. 2009;106(48):20270–5.

213. Nomura DK, Morrison BE, Blankman JL, Long JZ, Kinsey SG, Marcondes MCG, et al. Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science. 2011;334(6057):809–13.

214. Mulvihill MM, Nomura DK. Therapeutic potential of monoacylglycerol lipase inhibitors. Life Sci. 2013;92(8–9):492–7.

215. Nader J, Rapino C, Gennequin B, Chavant F, Francheteau M, Makriyannis A, et al. Prior stimulation of the endocannabinoid system prevents methamphetamine-induced dopaminergic neurotoxicity in the striatum through activation of CB2 receptors. Neuropharmacology. 2014;87:214–21.

216. Blanco E, Pavón FJ, Palomino A, Luque-Rojas MJ, Serrano A, Rivera P, et al. Cocaine-induced behavioral sensitization is associated with changes in the expression of endocannabinoid and glutamatergic signaling systems in the mouse prefrontal cortex. Int J Neuropsychopharmacol. 2014. https://doi.org/10.1093/ijnp/pyu024.

217. Li W, Zhang C-L, Qiu Z-G. Differential expression of endocannabinoid system-related genes in the dorsal hippocampus following expression and reinstatement of morphine conditioned place preference in mice. Neurosci Lett. 2017;16(643):38–44.

218. Schlosburg JE, Carlson BLA, Ramesh D, Abdullah RA, Long JZ, Cravatt BF, et al. Inhibitors of endocannabinoid-metabolizing enzymes reduce precipitated withdrawal responses in THC-dependent mice. AAPS J. 2009;11(2):342–52.

219. Muldoon PP, Chen J, Harenza JL, Abdullah RA, Sim-Selley LJ, Cravatt BF, et al. Inhibition of monoacylglycerol lipase reduces nicotine withdrawal. Br J Pharmacol. 2015;172(3):869–82.

220. Gamage TF, Ignatowska-Jankowska BM, Muldoon PP, Cravatt BF, Damaj MI, Lichtman AH. Differential effects of endocannabinoid catabolic inhibitors on morphine withdrawal in mice. Drug Alcohol Depend. 2015;1(146):7–16.

221. 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;01(114):156–67.

222. Di Marzo V, Fontana A, Cadas H, Schinelli S, Cimino G, Schwartz JC, et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature. 1994;372(6507):686–91.

223. Beltramo M, Stella N, Calignano A, Lin SY, Makriyannis A, Piomelli D. Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science. 1997;277(5329):1094–7.

224. Hillard CJ, Edgemond WS, Jarrahian A, Campbell WB. Accumulation of N-arachidonoylethanolamine (anandamide) into cerebellar granule cells occurs via facilitated diffusion. J Neurochem. 1997;69(2):631–8.

225. Fegley D, Kathuria S, Mercier R, Li C, Goutopoulos A, Makriyannis A, et al. Anandamide transport is independent of fatty-acid amide hydrolase activity and is blocked by the hydrolysis-resistant inhibitor AM1172. Proc Natl Acad Sci USA. 2004;101(23):8756–61.

226. Gianessi CA, Groman SM, Thompson SL, Jiang M, van der Stelt M, Taylor JR. Endocannabinoid contributions to alcohol habits and motivation: relevance to treatment. Addict Biol. 2019;6:e12768.

227. 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.

228. Gamaleddin I, Guranda M, Scherma M, Fratta W, Makriyannis A, Vadivel SK, et al. AM404 attenuates reinstatement of nicotine seeking induced by nicotine-associated cues and nicotine priming but does not affect nicotine- and food-taking. J Psychopharmacol. 2013;27(6):564–71.

229. Scherma M, Justinová Z, Zanettini C, Panlilio LV, Mascia P, Fadda P, et al. The anandamide transport inhibitor AM404 reduces the rewarding effects of nicotine and nicotine-induced dopamine elevations in the nucleus accumbens shell in rats. Br J Pharmacol. 2012;165(8):2539–48.

230. Vlachou S, Nomikos GG, Panagis G. Effects of endocannabinoid neurotransmission modulators on brain stimulation reward. Psychopharmacology (Berl). 2006;188(3):293–305.

231. Vlachou S, Stamatopoulou F, Nomikos GG, Panagis G. Enhancement of endocannabinoid neurotransmission through CB1 cannabinoid receptors counteracts the reinforcing and psychostimulant effects of cocaine. Int J Neuropsychopharmacol. 2008;11(7):905–23.

232. Schindler CW, Scherma M, Redhi GH, Vadivel SK, Makriyannis A, Goldberg SR, et al. Self-administration of the anandamide transport inhibitor AM404 by squirrel monkeys. Psychopharmacology (Berl). 2016;233(10):1867–77.

233. Levin FR, Mariani JJ, Brooks DJ, Pavlicova M, Cheng W, Nunes EV. Dronabinol for the treatment of cannabis dependence: a randomized, double-blind, placebo-controlled trial. Drug Alcohol Depend. 2011;116(1–3):142–50.

234. Herrmann ES, Cooper ZD, Bedi G, Ramesh D, Reed SC, Comer SD, et al. Effects of zolpidem alone and in combination with nabilone on cannabis withdrawal and a laboratory model of relapse in cannabis users. Psychopharmacology (Berl). 2016;233(13):2469–78.

235. Vandrey R, Stitzer ML, Mintzer MZ, Huestis MA, Murray JA, Lee D. The dose effects of short-term dronabinol (oral THC) maintenance in daily cannabis users. Drug Alcohol Depend. 2013;128(1–2):64–70.

236. Haney M, Cooper ZD, Bedi G, Vosburg SK, Comer SD, Foltin RW. Nabilone decreases marijuana withdrawal and a laboratory measure of marijuana relapse. Neuropsychopharmacology. 2013;38(8):1557–65.

237. Levin FR, Mariani JJ, Pavlicova M, Brooks D, Glass A, Mahony A, et al. Dronabinol and lofexidine for cannabis use disorder: a randomized, double-blind, placebo-controlled trial. Drug Alcohol Depend. 2016;1(159):53–60.

238. Haney M, Hart CL, Vosburg SK, Comer SD, Reed SC, Foltin RW. Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse. Psychopharmacology (Berl). 2008;197(1):157–68.

239. Budney AJ, Vandrey RG, Hughes JR, Moore BA, Bahrenburg B. Oral delta-9-tetrahydrocannabinol suppresses cannabis withdrawal symptoms. Drug Alcohol Depend. 2007;86(1):22–9.

240. Haney M, Hart CL, Vosburg SK, Nasser J, Bennett A, Zubaran C, et al. Marijuana withdrawal in humans: effects of oral THC or divalproex. Neuropsychopharmacology. 2004;29(1):158–70.

241. Jicha CJ, Lofwall MR, Nuzzo PA, Babalonis S, Elayi SC, Walsh SL. Safety of oral dronabinol during opioid withdrawal in humans. Drug Alcohol Depend. 2015;1(157):179–83.

242. Bisaga A, Sullivan MA, Glass A, Mishlen K, Pavlicova M, Haney M, et al. The effects of dronabinol during detoxification and the initiation of treatment with extended release naltrexone. Drug Alcohol Depend. 2015;1(154):38–45.

243. Lofwall MR, Babalonis S, Nuzzo PA, Elayi SC, Walsh SL. Opioid withdrawal suppression efficacy of oral dronabinol in opioid dependent humans. Drug Alcohol Depend. 2016;1(164):143–50.

244. Samanta D. Cannabidiol: a review of clinical efficacy and safety in epilepsy. Pediatr Neurol. 2019;96:24–9.

245. Maroon J, Bost J. Review of the neurological benefits of phytocannabinoids. Surg Neurol Int. 2018;9:91.

246. Bisogno T, Hanuš L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol. 2001;134(4):845–52.

247. Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol. 2007;150(5):613–23.

248. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153(2):199–215.

249. Martínez-Pinilla E, Varani K, Reyes-Resina I, Angelats E, Vincenzi F, Ferreiro-Vera C, et al. Binding and signaling studies disclose a potential allosteric site for cannabidiol in cannabinoid CB2 receptors. Front Pharmacol. 2017;8:744.

250. Navarro G, Reyes-Resina I, Rivas-Santisteban R, Sánchez de Medina V, Morales P, Casano S, et al. Cannabidiol skews biased agonism at cannabinoid CB1 and CB2 receptors with smaller effect in CB1–CB2 heteroreceptor complexes. Biochem Pharmacol. 2018;157:148–58.

251. Tham M, Yilmaz O, Alaverdashvili M, Kelly MEM, Denovan-Wright EM, Laprairie RB. Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors. Br J Pharmacol. 2019;176(10):1455–69.

252. Luján MÁ, Castro-Zavala A, Alegre-Zurano L, Valverde O. Repeated Cannabidiol treatment reduces cocaine intake and modulates neural proliferation and CB1R expression in the mouse hippocampus. Neuropharmacology. 2018;143:163–75.

253. Galaj E, Bi G-H, Yang H-J, Xi Z-X. Cannabidiol attenuates the rewarding effects of cocaine by CB2, 5-TH1A and TRPV1 receptor mechanisms. Neuropharmacology. 2019. https://doi.org/10.1016/j.neuropharm.2019.107740.

254. Hay GL, Baracz SJ, Everett NA, Roberts J, Costa PA, Arnold JC, et al. Cannabidiol treatment reduces the motivation to self-administer methamphetamine and methamphetamine-primed relapse in rats. J Psychopharmacol (Oxford). 2018;32(12):1369–78.

255. Viudez-Martínez A, García-Gutiérrez MS, Navarrón CM, Morales-Calero MI, Navarrete F, Torres-Suárez AI, et al. Cannabidiol reduces ethanol consumption, motivation and relapse in mice. Addict Biol. 2018;23(1):154–64.

256. Ren Y, Whittard J, Higuera-Matas A, Morris CV, Hurd YL. Cannabidiol, a nonpsychotropic component of cannabis, inhibits cue-induced heroin seeking and normalizes discrete mesolimbic neuronal disturbances. J Neurosci. 2009;29(47):14764–9.

257. Bi G-H, Galaj E, He Y, Xi Z-X. Cannabidiol inhibits sucrose self-administration by CB1 and CB2 receptor mechanisms in rodents. Addict Biol. 2019;19:e12783.

258. 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.

259. Markos JR, Harris HM, Gul W, ElSohly MA, Sufka KJ. Effects of cannabidiol on morphine conditioned place preference in mice. Planta Med. 2018;84(4):221–4.

260. Parker LA, Burton P, Sorge RE, Yakiwchuk C, Mechoulam R. Effect of low doses of delta9-tetrahydrocannabinol and cannabidiol on the extinction of cocaine-induced and amphetamine-induced conditioned place preference learning in rats. Psychopharmacology (Berl). 2004;175(3):360–6.

261. Gonzalez-Cuevas G, Martin-Fardon R, Kerr TM, Stouffer DG, Parsons LH, Hammell DC, et al. Unique treatment potential of cannabidiol for the prevention of relapse to drug use: preclinical proof of principle. Neuropsychopharmacology. 2018;43(10):2036–45.

262. de Carvalho CR, Takahashi RN. Cannabidiol disrupts the reconsolidation of contextual drug-associated memories in Wistar rats. Addict Biol. 2017;22(3):742–51.

263. Karimi-Haghighi S, Haghparast A. Cannabidiol inhibits priming-induced reinstatement of methamphetamine in REM sleep deprived rats. Prog Neuropsychopharmacol Biol Psychiatry. 2018;02(82):307–13.

264. Bhargava HN. Effect of some cannabinoids on naloxone-precipitated abstinence in morphine-dependent mice. Psychopharmacology (Berl). 1976;49(3):267–70.

265. Vilela LR, Gomides LF, David BA, Antunes MM, Diniz AB, Moreira F de A, et al. Cannabidiol rescues acute hepatic toxicity and seizure induced by cocaine. Mediators Inflamm [Internet]; 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427116/. Cited 2 Mar 2019.

266. Taylor L, Gidal B, Blakey G, Tayo B, Morrison G. A phase I, randomized, double-blind, placebo-controlled, single ascending dose, multiple dose, and food effect trial of the safety, tolerability and pharmacokinetics of highly purified cannabidiol in healthy subjects. CNS Drugs. 2018;32(11):1053–67.

267. Schoedel KA, Szeto I, Setnik B, Sellers EM, Levy-Cooperman N, Mills C, et al. Abuse potential assessment of cannabidiol (CBD) in recreational polydrug users: a randomized, double-blind, controlled trial. Epilepsy Behav. 2018;1(88):162–71.

268. Manini AF, Yiannoulos G, Bergamaschi MM, Hernandez S, Olmedo R, Barnes AJ, et al. Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans. J Addict Med. 2015;9:204–10.

269. Dalton WS, Martz R, Lemberger L, Rodda BE, Forney RB. Influence of cannabidiol on delta-9-tetrahydrocannabinol effects. Clin Pharmacol Ther. 1976;19(3):300–9.

270. Karniol IG, Shirakawa I, Kasinski N, Pfeferman A, Carlini EA. Cannabidiol interferes with the effects of delta 9—tetrahydrocannabinol in man. Eur J Pharmacol. 1974;28(1):172–7.

271. Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology (Berl). 1982;76(3):245–50.

272. Haney M, Malcolm RJ, Babalonis S, Nuzzo PA, Cooper ZD, Bedi G, et al. Oral cannabidiol does not alter the subjective, reinforcing or cardiovascular effects of smoked cannabis. Neuropsychopharmacology. 2016;41(8):1974–82.

273. Solowij N, Broyd S, Greenwood L-M, van Hell H, Martelozzo D, Rueb K, et al. A randomised controlled trial of vaporised Δ9-tetrahydrocannabinol and cannabidiol alone and in combination in frequent and infrequent cannabis users: acute intoxication effects. Eur Arch Psychiatry Clin Neurosci. 2019;269(1):17–35.

274. Allsop DJ, Copeland J, Lintzeris N, Dunlop AJ, Montebello M, Sadler C, et al. Nabiximols as an agonist replacement therapy during cannabis withdrawal: a randomized clinical trial. JAMA Psychiatry. 2014;71(3):281–91.

275. Trigo JM, Soliman A, Quilty LC, Fischer B, Rehm J, Selby P, et al. Nabiximols combined with motivational enhancement/cognitive behavioral therapy for the treatment of cannabis dependence: a pilot randomized clinical trial. PLoS One. 2018;13(1):e0190768.

276. Mediavilla V, Steinemann S. Essential oil of Cannabis sativa L strains. J Int Hemp Assoc. 1997;4:82–4.

277. Sharma C, Al Kaabi JM, Nurulain SM, Goyal SN, Kamal MA, Ojha S. Polypharmacological properties and therapeutic potential of β-caryophyllene: a dietary phytocannabinoid of pharmaceutical promise. Curr Pharm Des. 2016;22(21):3237–64.

278. Corey EJ, Mitra RB, Hisashi U. Total synthesis of d, l-caryophyllene and d, l-isocaryophyllene. J Am Chem Soc. 1964;86(3):485–92.

279. Gertsch J, Leonti M, Raduner S, Racz I, Chen J-Z, Xie X-Q, et al. Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci USA. 2008;105(26):9099–104.

280. Varga ZV, Matyas C, Erdelyi K, Cinar R, Nieri D, Chicca A, et al. β-Caryophyllene protects against alcoholic steatohepatitis by attenuating inflammation and metabolic dysregulation in mice. Br J Pharmacol. 2018;175(2):320–34.

281. Liu H, Yang G, Tang Y, Cao D, Qi T, Qi Y, et al. Physicochemical characterization and pharmacokinetics evaluation of β-caryophyllene/β-cyclodextrin inclusion complex. Int J Pharm. 2013;450(1–2):304–10.

282. Schmitt D, Levy R, Carroll B. Toxicological evaluation of β-caryophyllene oil: subchronic toxicity in rats. Int J Toxicol. 2016;35(5):558–67.

283. Oliveira GL da S, Machado KC, Machado KC, da Silva APDSCL, Feitosa CM, de Castro Almeida FR. Non-clinical toxicity of β-caryophyllene, a dietary cannabinoid: absence of adverse effects in female Swiss mice. Regul Toxicol Pharmacol. 2018;92:338–46.

284. Al Mansouri S, Ojha S, Al Maamari E, Al Ameri M, Nurulain SM, Bahi A. The cannabinoid receptor 2 agonist, β-caryophyllene, reduced voluntary alcohol intake and attenuated ethanol-induced place preference and sensitivity in mice. Pharmacol Biochem Behav. 2014;124:260–8.

285. Rose JE, Behm FM. Inhalation of vapor from black pepper extract reduces smoking withdrawal symptoms. Drug Alcohol Depend. 1994;34(3):225–9.

286. He Y, Galaj E, Bi GH, Wang XF, Gardner EL, Xi Z-X. Beta-caryophyllene: a dietary cannabis terpene, inhibits nicotine-taking and nicotine-seeking behavior in rodents. Br J Pharmacol. 2019 (in press).

287. Gill EW, Paton WDM, Pertwee RG. Preliminary experiments on the chemistry and pharmacology of cannabis. Nature. 1970;228:134–6.

288. Bolognini D, Costa B, Maione S, Comelli F, Marini P, Di Marzo V, et al. The plant cannabinoid Delta9-tetrahydrocannabivarin can decrease signs of inflammation and inflammatory pain in mice. Br J Pharmacol. 2010;160(3):677–87.

289. McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Δ(9)-tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172(3):737–53.

290. Thomas A, Stevenson LA, Wease KN, Price MR, Baillie G, Ross RA, et al. Evidence that the plant cannabinoid Delta9-tetrahydrocannabivarin is a cannabinoid CB1 and CB2 receptor antagonist. Br J Pharmacol. 2005;146(7):917–26.

291. Pertwee RG, Thomas A, Stevenson LA, Ross RA, Varvel SA, Lichtman AH, et al. The psychoactive plant cannabinoid, Delta9-tetrahydrocannabinol, is antagonized by Delta8- and Delta9-tetrahydrocannabivarin in mice in vivo. Br J Pharmacol. 2007;150(5):586–94.

292. Dennis I, Whalley BJ, Stephens GJ. Effects of Δ9-tetrahydrocannabivarin on [35S]GTPγS binding in mouse brain cerebellum and piriform cortex membranes. Br J Pharmacol. 2008;154(6):1349–58.

293. Hill AJ, Weston SE, Jones NA, Smith I, Bevan SA, Williamson EM, et al. Δ9-Tetrahydrocannabivarin suppresses in vitro epileptiform and in vivo seizure activity in adult rats. Epilepsia. 2010;51(8):1522–32.

294. Cascio MG, Zamberletti E, Marini P, Parolaro D, Pertwee RG. The phytocannabinoid, Δ9-tetrahydrocannabivarin, can act through 5-HT 1 A receptors to produce antipsychotic effects. Br J Pharmacol. 2015;172(5):1305–18.

295. De Petrocellis L, Ligresti A, Moriello AS, Allarà M, Bisogno T, Petrosino S, et al. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol. 2011;163(7):1479–94.

296. Janssens A, Silvestri C, Martella A, Vanoevelen JM, Di Marzo V, Voets T. Δ9-tetrahydrocannabivarin impairs epithelial calcium transport through inhibition of TRPV5 and TRPV6. Pharmacol Res. 2018;136:83–9.

297. Anavi-Goffer S, Baillie G, Irving AJ, Gertsch J, Greig IR, Pertwee RG, et al. Modulation of l-α-lysophosphatidylinositol/GPR55 mitogen-activated protein kinase (MAPK) signaling by cannabinoids. J Biol Chem. 2012;287(1):91–104.

298. Riedel G, Fadda P, McKillop-Smith S, Pertwee RG, Platt B, Robinson L. Synthetic and plant-derived cannabinoid receptor antagonists show hypophagic properties in fasted and non-fasted mice. Br J Pharmacol. 2009;156(7):1154–66.

299. Wargent ET, Zaibi MS, Silvestri C, Hislop DC, Stocker CJ, Stott CG, et al. The cannabinoid Δ(9)-tetrahydrocannabivarin (THCV) ameliorates insulin sensitivity in two mouse models of obesity. Nutr Diabetes. 2013;27(3):e68.

300. Bátkai S, Mukhopadhyay P, Horváth B, Rajesh M, Gao RY, Mahadevan A, et al. Δ8-Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors. Br J Pharmacol. 2012;165(8):2450–61.

301. Xi Z-X, Muldoon P, Wang XF, Bi G-H, Damaj IM, Lichtman AH, et al. Δ8-Tetrahydrocannabivarin has potent anti-nicotine effects in multiple rodent models of nicotine dependence. Br J Pharmacol. 2019. https://doi.org/10.1111/bph.14844.

302. Englund A, Atakan Z, Kralj A, Tunstall N, Murray R, Morrison P. The effect of five day dosing with THCV on THC-induced cognitive, psychological and physiological effects in healthy male human volunteers: a placebo-controlled, double-blind, crossover pilot trial. J Psychopharmacol (Oxford). 2016;30(2):140–51.

303. Jadoon KA, Ratcliffe SH, Barrett DA, Thomas EL, Stott C, Bell JD, et al. Efficacy and safety of cannabidiol and tetrahydrocannabivarin on glycemic and lipid parameters in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, parallel group pilot study. Diabetes Care. 2016;39(10):1777–86.