Cannabinoid treatment of opiate addiction


drug addiction
mouse models

How to Cite

McLemon, E., & Chesworth, R. (2021). Cannabinoid treatment of opiate addiction. Neuroanatomy and Behaviour, 3, e14.


Opioid abuse is a growing global problem. Current therapies for opioid abuse target withdrawal symptoms and have several adverse side effects. There are no treatments to address opioid-induced neural adaptations associated with abuse and addiction. Preclinical research demonstrates interactions between the endogenous opioid and cannabinoid systems, suggesting that cannabinoids may be used to treat opioid addiction and dependence. The aim of this review is to assess how cannabinoids affect behavioural and molecular measures of opioid dependence and addiction-like behaviour in animal models. It appears that cannabidiol and cannabinoid receptor 1 (CB1R) antagonists have potential for treating drug-craving and drug-seeking behaviour, based on evidence from preclinical animal models. Ligands which inhibit the action of cannabinoid degradation enzymes also show promise in reducing opioid withdrawal symptoms and opioid self-administration in rodents. Agonists of CB1R could be useful for treating symptoms of opioid withdrawal; however, the clinical utility of these drugs is limited by side effects, the potential for cannabinoid addiction and an increase in opiate tolerance induced by cannabinoid consumption. The mechanisms by which cannabinoids reduce opioid addiction-relevant behaviours include modulation of cannabinoid, serotonin, and dopamine receptors, as well as signalling cascades involving ERK-CREB-BDNF and peroxisome proliferator-activated receptor-α. Identifying the receptors involved and their mechanism of action remains a critical area of future research.


Blanch B, Pearson SA, Haber PS. An overview of the patterns of prescription opioid use, costs and related harms in Australia. Br J Clin Pharmacol. 2014;78(5):1159–66. doi: 10.1111/bcp.12446.

Strang J, Volkow ND, Degenhardt L, Hickman M, Johnson K, Koob GF, et al. Opioid use disorder. Nat Rev Dis Primers. 2020;6(1):3. doi: 10.1038/s41572-019-0137-5.

Harned M, Sloan P. Safety concerns with long-term opioid use. Expert Opin Drug Saf. 2016;15(7):955–62. doi: 10.1080/14740338.2016.1177509.

Kosten TR, Baxter LE. Review article: Effective management of opioid withdrawal symptoms: A gateway to opioid dependence treatment. Am J Addict. 2019;28(2):55–62. doi: 10.1111/ajad.12862.

Murnion B. Management of opioid substitution therapy during medical intervention. Intern Med J. 2012;42(3):242–6. doi: 10.1111/j.1445-5994.2012.02714.x.

Hurd YL, Yoon M, Manini AF, Hernandez S, Olmedo R, Ostman M, et al. Early Phase in the Development of Cannabidiol as a Treatment for Addiction: Opioid Relapse Takes Initial Center Stage. Neurotherapeutics. 2015;12(4):807–15. doi: 10.1007/s13311-015-0373-7.

Henry-Edwards S, Gowing L, White J, Ali R, Bell J, Brough R, et al. Clinical Guidelines and Procedures for the Use of Methadone in the Maintenance Treatment of Opioid Dependence. Canberra, Australia: Australian Government Department of Health and Ageing; 2003. OCLC: 224028040.

Lintzaris N, Clark N, Winstock A, Dunlop A, Muhleisen P, Gowing L, et al. National clinical guidelines and procedures for the use of buprenorphine in the treatment of opioid dependence. Canberra, Australia: Australian Government Department of Health and Ageing; 2006. OCLC: 225345629.

Kaufling J, Aston-Jones G. Persistent Adaptations in Afferents to Ventral Tegmental Dopamine Neurons after Opiate Withdrawal. J Neurosci. 2015;35(28):10290–303. doi: 10.1523/JNEUROSCI.0715-15.2015.

Welsch L, Bailly J, Darcq E, Kieffer BL. The Negative Affect of Protracted Opioid Abstinence: Progress and Perspectives From Rodent Models. Biol Psychiatry. 2020;87(1):54–63. doi: 10.1016/j.biopsych.2019.07.027.

Bergeria CL, Huhn AS, Dunn KE. The impact of naturalistic cannabis use on self-reported opioid withdrawal. J Subst Abuse Treat. 2020;113:108005. doi: 10.1016/j.jsat.2020.108005.

Kral AH, Wenger L, Novak SP, Chu D, Corsi KF, Coffa D, et al. Is cannabis use associated with less opioid use among people who inject drugs? Drug Alcohol Depend. 2015;153:236–41. doi: 10.1016/j.drugalcdep.2015.05.014.

Kim JH, Santaella-Tenorio J, Mauro C, Wrobel J, Cerda M, Keyes KM, et al. State Medical Marijuana Laws and the Prevalence of Opioids Detected Among Fatally Injured Drivers. Am J Public Health. 2016;106(11):2032–2037. doi: 10.2105/AJPH.2016.303426.

Scavone JL, Sterling RC, Van Bockstaele EJ. Cannabinoid and opioid interactions: implications for opiate dependence and withdrawal. Neuroscience. 2013;248:637–54. doi: 10.1016/j.neuroscience.2013.04.034.

Fattore L, Deiana S, Spano SM, Cossu G, Fadda P, Scherma M, et al. Endocannabinoid system and opioid addiction: behavioural aspects. Pharmacol Biochem Behav. 2005;81(2):343–59. doi: 10.1016/j.pbb.2005.01.031.

Robledo P, Berrendero F, Ozaita A, Maldonado R. Advances in the field of cannabinoid–opioid cross-talk. Addict Biol. 2008;13(2):213–24. doi: 10.1111/j.1369-1600.2008.00107.x.

Mansour A, Fox CA, Akil H, Watson SJ. Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications. Trends Neurosci. 1995;18(1):22–9. doi: 10.1016/0166-2236(95)93946-u.

Kieffer BL, Gaveriaux-Ruff C. Exploring the opioid system by gene knockout. Prog Neurobiol. 2002;66(5):285–306. doi: 10.1016/s0301-0082(02)00008-4.

Rodriguez JJ, Mackie K, Pickel VM. Ultrastructural localization of the CB1 cannabinoid receptor in mu-opioid receptor patches of the rat Caudate putamen nucleus. J Neurosci. 2001;21(3):823–33. doi: 10.1523/JNEUROSCI.21-03-00823.2001.

Law PY, Wong YH, Loh HH. Molecular mechanisms and regulation of opioid receptor signaling. Annu Rev Pharmacol Toxicol. 2000;40:389–430. doi: 10.1146/annurev.pharmtox.40.1.389.

Charbogne P, Kieffer BL, Befort K. 15 years of genetic approaches in vivo for addiction research: Opioid receptor and peptide gene knockout in mouse models of drug abuse. Neuropharmacology. 2014;76 Pt B:204–17. doi: 10.1016/j.neuropharm.2013.08.028.

Bailey CP, Husbands SM. Novel approaches for the treatment of psychostimulant and opioid abuse - focus on opioid receptor-based therapies. Expert Opin Drug Discov. 2014;9(11):1333–44. doi: 10.1517/17460441.2014.964203.

Bhargava HN. Multiple opiate receptors of brain and spinal cord in opiate addiction. Gen Pharmacol. 1991;22(5):767–72. doi: 10.1016/0306-3623(91)90202-h.

Chartoff EH, Connery HS. It’s MORe exciting than mu: crosstalk between mu opioid receptors and glutamatergic transmission in the mesolimbic dopamine system. Front Pharmacol. 2014;5:116. doi: 10.3389/fphar.2014.00116.

Kalivas PW. The glutamate homeostasis hypothesis of addiction. Nat Rev Neurosci. 2009;10(8):561–72. doi: 10.1038/nrn2515.

Bisogno T, Ligresti A, Di Marzo V. The endocannabinoid signalling system: biochemical aspects. Pharmacol Biochem Behav. 2005;81(2):224–38. doi: 10.1016/j.pbb.2005.01.027.

Keimpema E, Mackie K, Harkany T. Molecular model of cannabis sensitivity in developing neuronal circuits. Trends Pharmacol Sci. 2011;32(9):551–61. doi: 10.1016/

Chen DJ, Gao M, Gao FF, Su QX, Wu J. Brain cannabinoid receptor 2: expression, function and modulation. Acta Pharmacol Sin. 2017;38(3):312–316. doi: 10.1038/aps.2016.149.

Mallipeddi S, Janero DR, Zvonok N, Makriyannis A. Functional selectivity at G-protein coupled receptors: Advancing cannabinoid receptors as drug targets. Biochem Pharmacol. 2017;128:1–11. doi: 10.1016/j.bcp.2016.11.014.

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. doi: 10.1016/0306-4522(92)90409-u.

Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A. 1990;87(5):1932–6. PMID: 2308954.

Chye Y, Christensen E, Solowij N, Yucel M. The Endocannabinoid System and Cannabidiol’s Promise for the Treatment of Substance Use Disorder. Front Psychiatry. 2019;10:63. doi: 10.3389/fpsyt.2019.00063.

Pugh J G, Mason J D J, Combs V, Welch SP. Involvement of dynorphin B in the antinociceptive effects of the cannabinoid CP55,940 in the spinal cord. J Pharmacol Exp Ther. 1997;281(2):730–7. PMID: 9152379.

Pugh J G, Smith PB, Dombrowski DS, Welch SP. The role of endogenous opioids in enhancing the antinociception produced by the combination of delta 9-tetrahydrocannabinol and morphine in the spinal cord. J Pharmacol Exp Ther. 1996;279(2):608–16. PMID: 8930163.

Shapira M, Gafni M, Sarne Y. Long-term interactions between opioid and cannabinoid agonists at the cellular level: cross-desensitization and downregulation. Brain Res. 2003;960(1-2):190–200. doi: 10.1016/s0006-8993(02)03842-8.

Welch SP, Eads M. Synergistic interactions of endogenous opioids and cannabinoid systems. Brain Res. 1999;848(1-2):183–90. doi: 10.1016/s0006-8993(99)01908-3.

Kathmann M, Flau K, Redmer A, Trankle C, Schlicker E. Cannabidiol is an allosteric modulator at mu- and deltaopioid receptors. Naunyn Schmiedebergs Arch Pharmacol. 2006;372(5):354–61. doi: 10.1007/s00210-006-0033-x.

Haller VL, Stevens DL, Welch SP. Modulation of opioids via protection of anandamide degradation by fatty acid amide hydrolase. Eur J Pharmacol. 2008;600(1-3):50–8. doi: 10.1016/j.ejphar.2008.08.005.

Navarro M, Carrera MR, Fratta W, Valverde O, Cossu G, Fattore L, et al. Functional interaction between opioid and cannabinoid receptors in drug self-administration. J Neurosci. 2001;21(14):5344–50. doi: 10.1523/JNEUROSCI.21-14-05344.2001.

Gonzalez S, Schmid PC, Fernandez-Ruiz J, Krebsbach R, Schmid HH, Ramos JA. Region-dependent changes in endocannabinoid transmission in the brain of morphinedependent rats. Addict Biol. 2003;8(2):159–66. doi: 10.1080/1355621031000117383.

Ghozland S, Matthes HW, Simonin F, Filliol D, Kieffer BL, Maldonado R. Motivational effects of cannabinoids are mediated by mu-opioid and kappa-opioid receptors. J Neurosci. 2002;22(3):1146–54. doi: 10.1523/JNEUROSCI.22-03-01146.2002.

Castane A, Robledo P, Matifas A, Kieffer BL, Maldonado R. Cannabinoid withdrawal syndrome is reduced in double mu and delta opioid receptor knockout mice. Eur J Neurosci. 2003;17(1):155–9. doi: 10.1046/j.1460-9568.2003.02409.x.

Hoffman AF, Lupica CR. Synaptic targets of Δ9-tetrahydrocannabinol in the central nervous system. Cold Spring Harb Perspect Med. 2013;3(8). doi: 10.1101/cshperspect.a012237.

Hine B, Friedman E, Torrelio M, Gershon S. Morphinedependent rats: blockade of precipitated abstinence by tetrahydrocannabinol. Science. 1975;187(4175):443–5. doi: 10.1126/science.1167428.

Bhargava HN. Effect of some cannabinoids on naloxoneprecipitated abstinence in morphine-dependent mice. Psychopharmacology (Berl). 1976;49(3):267–70. doi: 10.1007/BF00426828.

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;146:7–16. doi: 10.1016/j.drugalcdep.2014.11.015.

Bhargava HN. Time course of the effects of naturally occurring cannabinoids on morphine abstinence syndrome. Pharmacol Biochem Behav. 1978;8(1):7–11. doi: 10.1016/0091-3057(78)90115-6.

Bhargava HN. Inhibition of naloxone-induced withdrawal in morphine dependent mice by 1-trans-Δ9-tetrahydrocannabinol. Eur J Pharmacol. 1976;36(1):259–62. doi: 10.1016/0014-2999(76)90283-1.

Yamaguchi T, Hagiwara Y, Tanaka H, Sugiura T, Waku K, Shoyama Y, et al. Endogenous cannabinoid, 2-arachidonoylglycerol, attenuates naloxone-precipitated withdrawal signs in morphine-dependent mice. Brain Res. 2001;909(1-2):121–6. doi: 10.1016/s0006-8993(01)02655-5.

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;154:38–45. doi: 10.1016/j.drugalcdep.2015.05.013.

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;164:143–150. doi: 10.1016/j.drugalcdep.2016.05.002.

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;157:179–83. doi: 10.1016/j.drugalcdep.2015.09.031.

White NM. Reward or reinforcement: what’s the difference? Neurosci Biobehav Rev. 1989;13(2-3):181–6. doi: 10.1016/s0149-7634(89)80028-4.

Li JX, Koek W, France CP. Interactions between Δ9-tetrahydrocannabinol and heroin: self-administration in rhesus monkeys. Behav Pharmacol. 2012;23(8):754–61. doi: 10.1097/FBP.0b013e32835a3907.

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

Solinas M, Goldberg SR. Motivational effects of cannabinoids and opioids on food reinforcement depend on simultaneous activation of cannabinoid and opioid systems. Neuropsychopharmacology. 2005;30(11):2035–45. doi: 10.1038/sj.npp.1300720.

Hudson R, Renard J, Norris C, Rushlow WJ, Laviolette SR. Cannabidiol Counteracts the Psychotropic Side-Effects of Δ-9-Tetrahydrocannabinol in the Ventral Hippocampus through Bidirectional Control of ERK1-2 Phosphorylation. J Neurosci. 2019;39(44):8762–8777. doi: 10.1523/JNEUROSCI.0708-19.2019.

Fattore L, Spano MS, Cossu G, Deiana S, Fratta W. Cannabinoid mechanism in reinstatement of heroin-seeking after a long period of abstinence in rats. Eur J Neurosci. 2003;17(8):1723–6. doi: 10.1046/j.1460-9568.2003.02607.x.

Schneider M. Puberty as a highly vulnerable developmental period for the consequences of cannabis exposure. Addict Biol. 2008;13(2):253–63. doi: 10.1111/j.1369-1600.2008.00110.x.

Ellgren M, Spano SM, Hurd YL. Adolescent cannabis exposure alters opiate intake and opioid limbic neuronal populations in adult rats. Neuropsychopharmacology. 2007;32(3):607–15. doi: 10.1038/sj.npp.1301127.

Solinas M, Panlilio LV, Goldberg SR. Exposure to Δ-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. doi: 10.1038/sj.npp.1300431.

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. doi: 10.1016/j.euroneuro.2013.12.012.

Cadoni C. Fischer 344 and Lewis Rat Strains as a Model of Genetic Vulnerability to Drug Addiction. Front Neurosci. 2016;10:13. doi: 10.3389/fnins.2016.00013.

Cadoni C, Simola N, Espa E, Fenu S, Di Chiara G. Strain dependence of adolescent Cannabis influence on heroin reward and mesolimbic dopamine transmission in adult Lewis and Fischer 344 rats. Addict Biol. 2015;20(1):132–42. doi: 10.1111/adb.12085.

Lecca D, Scifo A, Pisanu A, Valentini V, Piras G, Sil A, et al. Adolescent cannabis exposure increases heroin reinforcement in rats genetically vulnerable to addiction. Neuropharmacology. 2020;166:107974. doi: 10.1016/j.neuropharm.2020.107974.

Nguyen JD, Creehan KM, Kerr TM, Taffe MA. Lasting effects of repeated Δ9-tetrahydrocannabinol vapour inhalation during adolescence in male and female rats. Br J Pharmacol. 2020;177(1):188–203. doi: 10.1111/bph.14856.

Nguyen JD, Grant Y, Creehan KM, Hwang CS, Vandewater SA, Janda KD, et al. Δ9-tetrahydrocannabinol attenuates oxycodone self-administration under extended access conditions. Neuropharmacology. 2019;151:127–135. doi: 10.1016/j.neuropharm.2019.04.010.

Romanelli L, Palmery M, Tucci P, Amico MC, Morrone LA, Valeri P. Involvement of the cannabinoid CB1 receptor in the opioid inhibition of the response to cholecystokinin and acute withdrawal response. Neurotoxicology. 2005;26(5):819–27. doi: 10.1016/j.neuro.2005.03.010.

Manzanedo C, Aguilar MA, Rodriguez-Arias M, Navarro M, Minarro J. Cannabinoid agonist induced sensitisation to morphine place preference in mice. Neuroreport. 2004;15(8):1373–7. doi: 10.1097/01.wnr.0000126217.87116.8c.

Haghparast A, Shamsizadeh A, Samandari R, Omranifard A, Vaziri A, Razavi Y. Cannabinoid receptors in the basolateral amygdala are involved in the potentiation of morphine rewarding properties in the acquisition, but not expression of conditioned place preference in rats. Brain Res. 2014;1565:28–36. doi: 10.1016/j.brainres.2014.04.003.

Norwood CS, Cornish JL, Mallet PE, McGregor IS. Preexposure to the cannabinoid receptor agonist CP 55940 enhances morphine behavioral sensitization and alters morphine self-administration in Lewis rats. Eur J Pharmacol. 2003;465(1-2):105–14. doi: 10.1016/s0014-2999(03)01455-9.

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. doi: 10.1038/sj.npp.1300754.

Maguire DR, Yang W, France CP. Interactions between μ-opioid receptor agonists and cannabinoid receptor agonists in rhesus monkeys: antinociception, drug discrimination, and drug self-administration. J Pharmacol Exp Ther. 2013;345(3):354–62. doi: 10.1124/jpet.113.204099.

Braida D, Pozzi M, Parolaro D, Sala M. Intracerebral self-administration of the cannabinoid receptor agonist CP55,940 in the rat: interaction with the opioid system. Eur J Pharmacol. 2001;413(2-3):227–34. doi: 10.1016/s0014-2999(01)00766-x.

Braida D, Pozzi M, Cavallini R, Sala M. Conditioned place preference induced by the cannabinoid agonist CP55,940: interaction with the opioid system. Neuroscience. 2001;104(4):923–6. doi: 10.1016/s0306-4522(01)00210-x.

Ahmad T, Sun N, Lyons D, Laviolette SR. Bi-directional cannabinoid signalling in the basolateral amygdala controls rewarding and aversive emotional processing via functional regulation of the nucleus accumbens. Addict Biol. 2017;22(5):1218–1231. doi: 10.1111/adb.12406.

De Vries TJ, Homberg JR, Binnekade R, Raaso H, Schoffelmeer ANM. Cannabinoid modulation of the reinforcing and motivational properties of heroin and heroin-associated cues in rats. Psychopharmacology (Berl). 2003;168(1-2):164–169. doi: 10.1007/s00213-003-1422-1.

Khaleghzadeh-Ahangar H, Haghparast A. Intra-accumbal Cannabinoid Agonist Attenuated Reinstatement but not Extinction Period of Morphine-Induced Conditioned Place Preference; Evidence for Different Characteristics of Extinction Period and Reinstatement. Neurochem Res. 2017;42(11):3321–3330. doi: 10.1007/s11064-017-2374-x.

Khaleghzadeh-Ahangar H, Khodagholi F, Shaerzadeh F, Haghparast A. Modulatory role of the intra-accumbal CB1 receptor in protein level of the c-fos and pCREB/CREB ratio in the nucleus accumbens and ventral tegmental area in extinction and morphine seeking in the rats. Brain Res Bull. 2018;142:320–327. doi: 10.1016/j.brainresbull.2018.08.017.

Khaleghzadeh-Ahangar H, Haghparast A. Cannabinoid receptor modulation changes the accumbal neuronal responses to morphine in the reinstatement of morphine-induced conditioned place preference. Addict Biol. 2019; p. e12817. doi: 10.1111/adb.12817.

O’Neal TJ, Nooney MN, Thien K, Ferguson SM. Chemogenetic modulation of accumbens direct or indirect pathways bidirectionally alters reinstatement of heroin-seeking in high- but not low-risk rats. Neuropsychopharmacology. 2020;45(8):1251–1262. doi: 10.1038/s41386-019-0571-9.

Bossert JM, Adhikary S, St Laurent R, Marchant NJ, Wang HL, Morales M, et al. Role of projections from ventral subiculum to nucleus accumbens shell in context-induced reinstatement of heroin seeking in rats. Psychopharmacology (Berl). 2016;233(10):1991–2004. doi: 10.1007/s00213-015-4060-5.

Hearing MC, Jedynak J, Ebner SR, Ingebretson A, Asp AJ, Fischer RA, et al. Reversal of morphine-induced cell type-specific synaptic plasticity in the nucleus accumbens shell blocks reinstatement. Proc Natl Acad Sci U S A. 2016;113(3):757–62. doi: 10.1073/pnas.1519248113.

Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153(2):199–215. doi: 10.1038/sj.bjp.0707442.

Galaj E, Xi ZX. Possible Receptor Mechanisms Underlying Cannabidiol Effects on Addictive-like Behaviors in Experimental Animals. Int J Mol Sci. 2020;22(1). doi: 10.3390/ijms22010134.

Campos AC, Ferreira FR, Guimaraes FS. Cannabidiol blocks long-lasting behavioral consequences of predator threat stress: possible involvement of 5HT1A receptors. J Psychiatr Res. 2012;46(11):1501–10. doi: 10.1016/j.jpsychires.2012.08.012.

Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res. 2005;30(8):1037–43. doi: 10.1007/s11064-005-6978-1.

Laprairie RB, Bagher AM, Kelly ME, Denovan-Wright EM. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol. 2015;172(20):4790–805. doi: 10.1111/bph.13250.

Bisogno T, Hanus 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. doi: 10.1038/sj.bjp.0704327.

Hine B, Torrelio M, Gershon S. Differential effect of cannabinol and cannabidiol on THC-induced responses during abstinence in morphine-dependent rats. Res Commun Chem Pathol Pharmacol. 1975;12(1):185–8. PMID: 1237925.

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. doi: 10.1111/j.1369-1600.2012.00483.x.

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. doi: 10.1523/JNEUROSCI.4291-09.2009.

de Carvalho CR, Takahashi RN. Cannabidiol disrupts the reconsolidation of contextual drug-associated memories in Wistar rats. Addict Biol. 2017;22(3):742–751. doi: 10.1111/adb.12366.

Hurd YL, Spriggs S, Alishayev J, Winkel G, Gurgov K, Kudrich C, et al. Cannabidiol for the Reduction of Cue-Induced Craving and Anxiety in Drug-Abstinent Individuals With Heroin Use Disorder: A Double-Blind Randomized Placebo-Controlled Trial. Am J Psychiatry. 2019;176(11):911–922. doi: 10.1176/appi.ajp.2019.18101191.

Capano A, Weaver R, Burkman E. Evaluation of the effects of CBD hemp extract on opioid use and quality of life indicators in chronic pain patients: a prospective cohort study. Postgrad Med. 2020;132(1):56–61. doi: 10.1080/00325481.2019.1685298.

Galaj E, Xi ZX. Potential of Cannabinoid Receptor Ligands as Treatment for Substance Use Disorders. CNS Drugs. 2019;33(10):1001–1030. doi: 10.1007/s40263-019-00664-w.

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. doi: 10.1124/jpet.111.181370.

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. doi: 10.1016/j.brainresbull.2011.06.019.

Rock EM, Ayoub SM, Limebeer CL, Gene A, Wills KL, DeVuono MV, et al. Acute naloxone-precipitated morphine withdrawal elicits nausea-like somatic behaviors in rats in a manner suppressed by N-oleoylglycine. Psychopharmacology (Berl). 2020;237(2):375–384. doi: 10.1007/s00213-019-05373-2.

Ayoub SM, Smoum R, Farag M, Atwal H, Collins SA, Rock EM, et al. Oleoyl alanine (HU595): a stable monomethylated oleoyl glycine interferes with acute naloxone precipitated morphine withdrawal in male rats. Psychopharmacology (Berl). 2020;237(9):2753–2765. doi: 10.1007/s00213-020-05570-4.

Manwell LA, Satvat E, Lang ST, Allen CP, Leri F, Parker LA. FAAH inhibitor, URB-597, promotes extinction and CB1 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. doi: 10.1016/j.pbb.2009.08.002.

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. doi: 10.1016/j.pbb.2010.07.010.

Petrie GN, Wills KL, Piscitelli F, Smoum R, Limebeer CL, Rock EM, et al. Oleoyl glycine: interference with the aversive effects of acute naloxone-precipitated MWD, but not morphine reward, in male Sprague-Dawley rats. Psychopharmacology (Berl). 2019;236(9):2623–2633. doi: 10.1007/s00213-019-05237-9.

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. doi: 10.1007/s00213-014-3575-5.

Ramesh D, Gamage TF, Vanuytsel T, Owens RA, Abdullah RA, Niphakis MJ, et al. Dual inhibition of endocannabinoid catabolic enzymes produces enhanced antiwithdrawal effects in morphine-dependent mice. Neuropsychopharmacology. 2013;38(6):1039–49. doi: 10.1038/npp.2012.269.

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. doi: 10.1007/s00213-016-4211-3.

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. doi: 10.1177/0269881113477710.

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. doi: 10.1017/S1461145708008717.

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. doi: 10.4103/0976-500X.189661.

van Esbroeck ACM, Janssen APA, Cognetta r A B, 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):1084–1087. doi: 10.1126/science.aaf7497.

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 U S A. 2005;102(51):18620–5. doi: 10.1073/pnas.0509591102.

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. doi: 10.1111/j.1527-3458.2006.00021.x.

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. doi: 10.1016/j.biopsych.2008.08.008.

Wills KL, Petrie GN, Millett G, Limebeer CL, Rock EM, Niphakis MJ, et al. Double Dissociation of Monoacylglycerol Lipase Inhibition and CB1 Antagonism in the Central Amygdala, Basolateral Amygdala, and the Interoceptive Insular Cortex on the Affective Properties of Acute Naloxone-Precipitated Morphine Withdrawal in Rats. Neuropsychopharmacology. 2016;41(7):1865–73. doi: 10.1038/npp.2015.356.

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;114:156–167. doi: 10.1016/j.neuropharm.2016.11.015.

Navarro M, Chowen J, Rocio ACM, del Arco I, Villanua MA, Martin Y, et al. CB1 cannabinoid receptor antagonist-induced opiate withdrawal in morphine-dependent rats. Neuroreport. 1998;9(15):3397–402. doi: 10.1097/00001756-199810260-00012.

Mas-Nieto M, Pommier B, Tzavara ET, Caneparo A, Da Nascimento S, Le Fur G, et al. Reduction of opioid dependence by the CB1 antagonist SR141716A in mice: evaluation of the interest in pharmacotherapy of opioid addiction. Br J Pharmacol. 2001;132(8):1809–16. doi: 10.1038/sj.bjp.0703990.

Cossu G, Ledent C, Fattore L, Imperato A, Bohme GA, Parmentier M, et al. Cannabinoid CB1 receptor knockout mice fail to self-administer morphine but not other drugs of abuse. Behav Brain Res. 2001;118(1):61–5. doi: 10.1016/s0166-4328(00)00311-9.

Wills KL, DeVuono MV, Limebeer CL, Vemuri K, Makriyannis A, Parker LA. CB1 receptor antagonism in the bed nucleus of the stria terminalis interferes with affective opioid withdrawal in rats. Behav Neurosci. 2017;131(4):304–11. doi: 10.1037/bne0000201.

Yuan WX, Heng LJ, Ma J, Wang XQ, Qu LJ, Duan L, et al. Increased expression of cannabinoid receptor 1 in the nucleus accumbens core in a rat model with morphine withdrawal. Brain Res. 2013;1531:102–12. doi: 10.1016/j.brainres.2013.07.047.

Alvarez-Jaimes L, Polis I, Parsons LH. Attenuation of cue-induced heroin-seeking behavior by cannabinoid CB1 antagonist infusions into the nucleus accumbens core and prefrontal cortex, but not basolateral amygdala. Neuropsychopharmacology. 2008;33(10):2483–93. doi: 10.1038/sj.npp.1301630.

He XH, Jordan CJ, Vemuri K, Bi GH, 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(3):365–373. doi: 10.1038/s41401-018-0059-x.

Feja M, Leigh MPK, Baindur AN, McGraw JJ, Wakabayashi KT, Cravatt BF, et al. The novel MAGL inhibitor MJN110 enhances responding to reward-predictive incentive cues by activation of CB1 receptors. Neuropharmacology. 2020;162:107814. doi: 10.1016/j.neuropharm.2019.107814.

Zhang J, Wang N, Chen B, Wang Y, He J, Cai X, et al. Blockade of Cannabinoid CB1 receptor attenuates the acquisition of morphine-induced conditioned place preference along with a downregulation of ERK, CREB phosphorylation, and BDNF expression in the nucleus accumbens and hippocampus. Neurosci Lett. 2016;630:70–76. doi: 10.1016/j.neulet.2016.07.047.

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

Zhao X, Yao L, Wang F, Zhang H, Wu L. Cannabinoid 1 receptor blockade in the dorsal hippocampus prevents the reinstatement but not acquisition of morphine-induced conditioned place preference in rats. Neuroreport. 2017;28(10):565–570. doi: 10.1097/WNR.0000000000000796.

Pan B, Zhong P, Sun D, Liu QS. Extracellular signalregulated kinase signaling in the ventral tegmental area mediates cocaine-induced synaptic plasticity and rewarding effects. J Neurosci. 2011;31(31):11244–55. doi: 10.1523/JNEUROSCI.1040-11.2011.

Lv XF, Sun LL, Cui CL, Han JS. NAc Shell Arc/Arg3.1 Protein Mediates Reconsolidation of Morphine CPP by Increased GluR1 Cell Surface Expression: Activation of ERK-Coupled CREB is Required. Int J Neuropsychopharmacol. 2015;18(9). doi: 10.1093/ijnp/pyv030.

Haghparast A, Azizi P, Hassanpour-Ezatti M, Khorrami H, Naderi N. Sub-chronic administration of AM251, CB1 receptor antagonist, within the nucleus accumbens induced sensitization to morphine in the rat. Neurosci Lett. 2009;467(1):43–7. doi: 10.1016/j.neulet.2009.09.062.

Ahmad T, Lauzon NM, de Jaeger X, Laviolette SR. Cannabinoid transmission in the prelimbic cortex bidirectionally controls opiate reward and aversion signaling through dissociable kappa versus μ-opiate receptor dependent mechanisms. J Neurosci. 2013;33(39):15642–51. doi: 10.1523/JNEUROSCI.1686-13.2013.

Iyer V, Slivicki RA, Thomaz AC, Crystal JD, Mackie K, Hohmann AG. The cannabinoid CB2 receptor agonist LY2828360 synergizes with morphine to suppress neuropathic nociception and attenuates morphine reward and physical dependence. Eur J Pharmacol. 2020;886:173544. doi: 10.1016/j.ejphar.2020.173544.

Lin X, Dhopeshwarkar AS, Huibregtse M, Mackie K, Hohmann AG. Slowly signaling G protein–biased CB2 cannabinoid receptor agonist LY2828360 suppresses neuropathic pain with sustained efficacy and attenuates morphine tolerance and dependence. Mol Pharmacol. 2018;93(2):49–62. doi: 10.1124/mol.117.109355.

Li AL, 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):155–168. doi: 10.1124/mol.118.113233.

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):1113–1129. doi: 10.1016/j.jpain.2018.04.009.

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. doi: 10.1016/j.neuropharm.2016.12.008.

Marconi A, Di Forti M, Lewis CM,A Murray RM, Vassos E. Metaanalysis of the Association Between the Level of Cannabis Use and Risk of Psychosis. Schizophr Bull. 2016;42(5):1262–9. doi: 10.1093/schbul/sbw003.

Navarrete F, Garcia-Gutierrez MS, Manzanares J. Pharmacological regulation of cannabinoid CB2 receptor modulates the reinforcing and motivational actions of ethanol. Biochem Pharmacol. 2018;157:227–234. doi: 10.1016/j.bcp.2018.07.041.

Xi ZX, Peng XQ, Li X, Song R, Zhang HY, Liu QR, et al. Brain cannabinoid CB2 receptors modulate cocaine’s actions in mice. Nat Neurosci. 2011;14(9):1160–6. doi: 10.1038/nn.2874.

Piazza PV, Deroche-Gamonet V. A multistep general theory of transition to addiction. Psychopharmacology (Berl). 2013;229(3):387–413. doi: 10.1007/s00213-013-3224-4.

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