Advertisement

Neurotransmitter and Neuropeptide Targets for Cannabis Use Disorder Treatment

  • Brian J. Sherman
  • Aimee L. McRae-ClarkEmail author
Chapter

Abstract

Increasing prevalence rates of cannabis use and cannabis use disorders underscore the need for more effective interventions. Potential pharmacotherapeutic targets include serotonergic, dopaminergic, and noradrenergic neurotransmitter systems, as well as the oxytocinergic neuropeptide system. However, numerous medications have been tested and results have been limited to date. Serotonergic agents (SSRIs) were initially efficacious in samples with comorbid substance use and psychiatric disorders, but controlled trials for cannabis use disorder have been largely negative. Studies investigating dopaminergic agents have shown some efficacy in reducing cannabis craving but limited positive effects on cannabis use. Noradrenergic agents, while also initially promising, have shown null effects on cannabis use or in some cases had worse outcomes. Oxytocin has shown promise in reducing cannabis use, yet fully powered clinical trials have not been conducted. Additional work is necessary to develop effective pharmacotherapies for cannabis use disorder.

Keywords

Serotonin Norepinephrine Dopamine Oxytocin Pharmacotherapy 

References

  1. 1.
    Agrawal A, Pergadia ML, Lynskey MT. Is there evidence for symptoms of cannabis withdrawal in the national epidemiologic survey of alcohol and related conditions? Am J Addict. 2008;17(3):199–208.CrossRefGoogle Scholar
  2. 2.
    Aston-Jones G, Kalivas PW. Brain norepinephrine rediscovered in addiction research. Biol Psychiatry. 2008;63(11):1005–6.CrossRefGoogle Scholar
  3. 3.
    Bambico FR, Katz N, Debonnel G, Gobbi G. Cannabinoids elicit antidepressant-like behavior and activate serotonergic neurons through the medial prefrontal cortex. J Neurosci. 2007;27(43):11700–11.CrossRefGoogle Scholar
  4. 4.
    Bloomfield MA, Ashok AH, Volkow ND, Howes OD. The effects of Delta9-tetrahydrocannabinol on the dopamine system. Nature. 2016;539(7629):369–77.CrossRefGoogle Scholar
  5. 5.
    Budney AJ, Hughes JR. The cannabis withdrawal syndrome. Curr Opin Psychiatry. 2006;19(3):233–8.CrossRefGoogle Scholar
  6. 6.
    Carpenter KM, McDowell D, Brooks DJ, Cheng WY, Levin FR. A preliminary trial: double-blind comparison of nefazodone, bupropion-SR, and placebo in the treatment of cannabis dependence. Am J Addict. 2009;18(1):53–64.CrossRefGoogle Scholar
  7. 7.
    Cornelius JR, Bukstein OG, Douaihy AB, Clark DB, Chung TA, Daley DC, et al. Double-blind fluoxetine trial in comorbid MDD-CUD youth and young adults. Drug Alcohol Depend. 2010;112(1–2):39–45.CrossRefGoogle Scholar
  8. 8.
    Cornelius JR, Salloum IM, Haskett RF, Ehler JG, Jarrett PJ, Thase ME, et al. Fluoxetine versus placebo for the marijuana use of depressed alcoholics. Addict Behav. 1999;24(1):111–4.CrossRefGoogle Scholar
  9. 9.
    Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A. 1988;85(14):5274–8.CrossRefGoogle Scholar
  10. 10.
    Goldstein RZ, Volkow ND. Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nat Rev Neurosci. 2011;12(11):652–69.CrossRefGoogle Scholar
  11. 11.
    Gomes FV, Resstel LB, Guimaraes FS. The anxiolytic-like effects of cannabidiol injected into the bed nucleus of the stria terminalis are mediated by 5-HT1A receptors. Psychopharmacology. 2011;213(2–3):465–73.CrossRefGoogle Scholar
  12. 12.
    Hasin DS. U.S. epidemiology of cannabis use and associated problems. Neuropsychopharmacology. 2017;43(1):195–212.CrossRefGoogle Scholar
  13. 13.
    Hasin DS, Kerridge BT, Saha TD, Huang B, Pickering R, Smith SM, et al. Prevalence and correlates of DSM-5 cannabis use disorder, 2012-2013: findings from the National Epidemiologic Survey on Alcohol and Related Conditions-III. Am J Psychiatry. 2016;173(6):588–99.CrossRefGoogle Scholar
  14. 14.
    Hill MN, McEwen BS. Involvement of the endocannabinoid system in the neurobehavioural effects of stress and glucocorticoids. Prog Neuro-Psychopharmacol Biol Psychiatry. 2010;34(5):791–7.CrossRefGoogle Scholar
  15. 15.
    Jezova D, Skultetyova I, Tokarev DI, Bakos P, Vigas M. Vasopressin and oxytocin in stress. Ann N Y Acad Sci. 1995;771:192–203.CrossRefGoogle Scholar
  16. 16.
    Kelly MA, Pavlicova M, Glass A, Mariani JJ, Bisaga A, Sullivan MA, et al. Do withdrawal-like symptoms mediate increased marijuana smoking in individuals treated with venlafaxine-XR? Drug Alcohol Depend. 2014;144:42–6.CrossRefGoogle Scholar
  17. 17.
    Kovacs GL, Sarnyai Z, Szabo G. Oxytocin and addiction: a review. Psychoneuroendocrinology. 1998;23(8):945–62.CrossRefGoogle Scholar
  18. 18.
    Lader M. Can buspirone induce rebound, dependence or abuse? Br J Psychiatry Suppl. 1991;159(12):45–51.CrossRefGoogle Scholar
  19. 19.
    Levin FR, Mariani J, Brooks DJ, Pavlicova M, Nunes EV, Agosti V, et al. A randomized double-blind, placebo-controlled trial of venlafaxine-extended release for co-occurring cannabis dependence and depressive disorders. Addiction. 2013;108(6):1084–94.CrossRefGoogle Scholar
  20. 20.
    Liberzon I, Trujillo KA, Akil H, Young EA. Motivational properties of oxytocin in the conditioned place preference paradigm. Neuropsychopharmacology. 1997;17(6):353–9.CrossRefGoogle Scholar
  21. 21.
    Light KC, Grewen KM, Amico JA, Boccia M, Brownley KA, Johns JM. Deficits in plasma oxytocin responses and increased negative affect, stress, and blood pressure in mothers with cocaine exposure during pregnancy. Addict Behav. 2004;29(8):1541–64.CrossRefGoogle Scholar
  22. 22.
    Ling W, Chang L, Hillhouse M, Ang A, Striebel J, Jenkins J, et al. Sustained-release methylphenidate in a randomized trial of treatment of methamphetamine use disorder. Addiction. 2014;109(9):1489–500.CrossRefGoogle Scholar
  23. 23.
    Ludwig M, Leng G. Dendritic peptide release and peptide-dependent behaviours. Nat Rev Neurosci. 2006;7(2):126–36.CrossRefGoogle Scholar
  24. 24.
    Mato S, Vidal R, Castro E, Diaz A, Pazos A, Valdizan EM. Long-term fluoxetine treatment modulates cannabinoid type 1 receptor-mediated inhibition of adenylyl cyclase in the rat prefrontal cortex through 5-hydroxytryptamine 1A receptor-dependent mechanisms. Mol Pharmacol. 2010;77(3):424–34.CrossRefGoogle Scholar
  25. 25.
    McRae-Clark AL, Baker NL, Gray KM, Killeen T, Hartwell KJ, Simonian SJ. Vilazodone for cannabis dependence: a randomized, controlled pilot trial. Am J Addict. 2016;25(1):69–75.CrossRefGoogle Scholar
  26. 26.
    McRae-Clark AL, Baker NL, Gray KM, Killeen TK, Wagner AM, Brady KT, et al. Buspirone treatment of cannabis dependence: a randomized, placebo-controlled trial. Drug Alcohol Depend. 2015;156:29–37.CrossRefGoogle Scholar
  27. 27.
    McRae-Clark AL, Baker NL, Maria MM, Brady KT. Effect of oxytocin on craving and stress response in marijuana-dependent individuals: a pilot study. Psychopharmacology. 2013;228(4):623–31.CrossRefGoogle Scholar
  28. 28.
    McRae-Clark AL, Carter RE, Killeen TK, Carpenter MJ, Wahlquist AE, Simpson SA, et al. A placebo-controlled trial of buspirone for the treatment of marijuana dependence. Drug Alcohol Depend. 2009;105(1–2):132–8.CrossRefGoogle Scholar
  29. 29.
    McRae-Clark AL, Carter RE, Killeen TK, Carpenter MJ, White KG, Brady KT. A placebo-controlled trial of atomoxetine in marijuana-dependent individuals with attention deficit hyperactivity disorder. Am J Addict. 2010;19(6):481–9.CrossRefGoogle Scholar
  30. 30.
    Melis MR, Melis T, Cocco C, Succu S, Sanna F, Pillolla G, et al. Oxytocin injected into the ventral tegmental area induces penile erection and increases extracellular dopamine in the nucleus accumbens and paraventricular nucleus of the hypothalamus of male rats. Eur J Neurosci. 2007;26(4):1026–35.CrossRefGoogle Scholar
  31. 31.
    Nordstrom BR, Levin FR. Treatment of cannabis use disorders: a review of the literature. Am J Addict. 2007;16(5):331–42.CrossRefGoogle Scholar
  32. 32.
    Notzon DP, Mariani JJ, Pavlicova M, Glass A, Mahony AL, Brooks DJ, et al. Mixed-amphetamine salts increase abstinence from marijuana in patients with co-occurring attention-deficit/hyperactivity disorder and cocaine dependence. Am J Addict. 2016;25(8):666–72.CrossRefGoogle Scholar
  33. 33.
    Pedersen CA, Smedley KL, Leserman J, Jarskog LF, Rau SW, Kampov-Polevoi A, et al. Intranasal oxytocin blocks alcohol withdrawal in human subjects. Alcohol Clin Exp Res. 2013;37(3):484–9.CrossRefGoogle Scholar
  34. 34.
    Penetar DM, Looby AR, Ryan ET, Maywalt MA, Lukas SE. Bupropion reduces some of the symptoms of marihuana withdrawal in chronic marihuana users: a pilot study. Subst Abuse. 2012;6:63–71.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res. 2005;30(8):1037–43.CrossRefGoogle Scholar
  36. 36.
    Sarnyai Z, Babarczy E, Krivan M, Szabo G, Kovacs GL, Barth T, et al. Selective attenuation of cocaine-induced stereotyped behaviour by oxytocin: putative role of basal forebrain target sites. Neuropeptides. 1991;19(1):51–6.CrossRefGoogle Scholar
  37. 37.
    Sarnyai Z, Biro E, Babarczy E, Vecsernyes M, Laczi F, Szabo G, et al. Oxytocin modulates behavioural adaptation to repeated treatment with cocaine in rats. Neuropharmacology. 1992;31(6):593–8.CrossRefGoogle Scholar
  38. 38.
    Sarnyai Z, Szabo G, Kovacs GL, Telegdy G. Opposite actions of oxytocin and vasopressin in the development of cocaine-induced behavioral sensitization in mice. Pharmacol Biochem Behav. 1992;43(2):491–4.CrossRefGoogle Scholar
  39. 39.
    Shafa R. COMT-inhibitors may be a promising tool in treatment of marijuana addiction. Am J Addict. 2009;18(4):322.Google Scholar
  40. 40.
    Sherman BJ, Baker NL, McRae-Clark AL. Effect of oxytocin pretreatment on cannabis outcomes in a brief motivational intervention. Psychiatry Res. 2017;249:318–20.CrossRefGoogle Scholar
  41. 41.
    Sherman BJ, McRae-Clark AL. Treatment of cannabis use disorder: current science and future outlook. Pharmacotherapy. 2016;36(5):511–35.CrossRefGoogle Scholar
  42. 42.
    Sherman BJ, McRae-Clark AL, Baker NL, Sonne SC, Killeen TK, Cloud K, et al. Gender differences among treatment-seeking adults with cannabis use disorder: clinical profiles of women and men enrolled in the achieving cannabis cessation-evaluating N-acetylcysteine treatment (ACCENT) study. Am J Addict. 2017;26(2):136–44.CrossRefGoogle Scholar
  43. 43.
    Sivukhina EV, Dolzhikov AA, Morozov Iu E, Jirikowski GF, Grinevich V. Effects of chronic alcoholic disease on magnocellular and parvocellular hypothalamic neurons in men. Horm Metab Res. 2006;38(6):382–90.CrossRefGoogle Scholar
  44. 44.
    Stahl SM. Neurotransmission of cognition, part 2. Selective NRIs are smart drugs: exploiting regionally selective actions on both dopamine and norepinephrine to enhance cognition. J Clin Psychiatry. 2003;64(2):110–1.CrossRefGoogle Scholar
  45. 45.
    Stauffer CS, Musinipally V, Suen A, Lynch KL, Shapiro B, Woolley JD. A two-week pilot study of intranasal oxytocin for cocaine-dependent individuals receiving methadone maintenance treatment for opioid use disorder. Addict Res Theory. 2016;24(6):490–8.CrossRefGoogle Scholar
  46. 46.
    Stock S, Uvnas-Moberg K. Increased plasma levels of oxytocin in response to afferent electrical stimulation of the sciatic and vagal nerves and in response to touch and pinch in anaesthetized rats. Acta Physiol Scand. 1988;132(1):29–34.CrossRefGoogle Scholar
  47. 47.
    Tanda G, Pontieri FE, Di Chiara G. Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism. Science. 1997;276(5321):2048–50.CrossRefGoogle Scholar
  48. 48.
    Tirado CF, Goldman M, Lynch K, Kampman KM, Obrien CP. Atomoxetine for treatment of marijuana dependence: a report on the efficacy and high incidence of gastrointestinal adverse events in a pilot study. Drug Alcohol Depend. 2008;94(1–3):254–7.CrossRefGoogle Scholar
  49. 49.
    Uvnas-Moberg K, Bruzelius G, Alster P, Lundeberg T. The antinociceptive effect of non-noxious sensory stimulation is mediated partly through oxytocinergic mechanisms. Acta Physiol Scand. 1993;149(2):199–204.CrossRefGoogle Scholar
  50. 50.
    Vaccari C, Lolait SJ, Ostrowski NL. Comparative distribution of vasopressin V1b and oxytocin receptor messenger ribonucleic acids in brain. Endocrinology. 1998;139(12):5015–33.CrossRefGoogle Scholar
  51. 51.
    Vandrey R, Haney M. Pharmacotherapy for cannabis dependence: how close are we? CNS Drugs. 2009;23(7):543–53.CrossRefGoogle Scholar
  52. 52.
    Wei D, Lee D, Cox CD, Karsten CA, Penagarikano O, Geschwind DH, et al. Endocannabinoid signaling mediates oxytocin-driven social reward. Proc Natl Acad Sci U S A. 2015;112(45):14084–9.CrossRefGoogle Scholar
  53. 53.
    Weinshenker D, Schroeder JP. There and back again: a tale of norepinephrine and drug addiction. Neuropsychopharmacology. 2007;32(7):1433–51.CrossRefGoogle Scholar
  54. 54.
    Weinstein AM, Miller H, Bluvstein I, Rapoport E, Schreiber S, Bar-Hamburger R, et al. Treatment of cannabis dependence using escitalopram in combination with cognitive-behavior therapy: a double-blind placebo-controlled study. Am J Drug Alcohol Abuse. 2014;40(1):16–22.CrossRefGoogle Scholar
  55. 55.
    Wotjak CT, Ganster J, Kohl G, Holsboer F, Landgraf R, Engelmann M. Dissociated central and peripheral release of vasopressin, but not oxytocin, in response to repeated swim stress: new insights into the secretory capacities of peptidergic neurons. Neuroscience. 1998;85(4):1209–22.CrossRefGoogle Scholar
  56. 56.
    Zanelati TV, Biojone C, Moreira FA, Guimaraes FS, Joca SR. Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol. 2010;159(1):122–8.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Psychiatry and Behavioral Sciences, Medical University of South CarolinaCharlestonUSA
  2. 2.Office of Research Integrity, Ralph H. Johnson VA Medical CenterCharlestonUSA

Personalised recommendations