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What is the mechanism whereby cannabis use increases risk of psychosis?

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Abstract

Cannabis use has increased greatly over the last three decades. The various types of cannabis differ in their concentration of the main psychoactive component, Δ9-tetrahydrocannabinol (THC), and the other major ingredient, cannabidiol (CBD). Plant engineering has maximized levels of THC, thus increasing the potency of street cannabis. It is well known that cannabis intoxication can cause brief psychotic symptoms like paranoia, whilst recent evidence demonstrates that heavy use of cannabis increases the risk of chronic psychoses like schizophrenia; genetic vulnerability seems to predispose some people to a higher risk. This paper starts to consider the neurochemical mechanisms whereby cannabis use increases the risk of psychosis.

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References

  • Aguado T, J Palazuelos, K Monory, N Stella, B Cravatt, B Lutz, G Marsicano, Z Kokaia, M Guzman and I Galve-Roperh (2006) The endocannabinoid system promotes astroglial differentiation by acting on neural progenitor cells.J. Neurosci. 26, 1551–1561.

    Article  PubMed  CAS  Google Scholar 

  • Andréasson S, P Allebeck, A Engström and U Rydberg (1987) Cannabis and schizophrenia. A longitudinal study of Swedish conscripts.Lancet 2(8574), 1483–1486.

    Article  PubMed  Google Scholar 

  • Antonelli T, MC Tomasini, M Tattoli, T Cassano, S Tanganelli, S Finetti, E Mazzoni, L Trabace, L Steardo, V Cuomo and L Ferraro (2005) Prenatal exposure to the CB1receptor agonist WIN 55,212-2 causes learning disruption associated with impaired cortical NMDA receptor function and emotional reactivity changes in rat offspring.Cereb. Cortex 15, 2013–2020.

    Article  PubMed  Google Scholar 

  • Arseneault L, M Cannon, R Poulton, R Murray, A Caspi and TE Moffit (2002) Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study.Br. Med. J. 7374, 1212–1213.

    Article  Google Scholar 

  • Arseneault L, M Cannon, J Witton and RM Murray (2004) Causal association between cannabis and psychosis: examination of the evidence.Br. J. Psychiatry 184, 110–117.

    Article  PubMed  Google Scholar 

  • Ashton H (2002) Cannabis or health?Curr. Opin. Psychiatry 15, 247–253.

    Article  Google Scholar 

  • Bailey CH, M Giustetto, YY Huang, RD Hawkins and ER Kandel (2000) Is heterosynaptic modulation essential for stabilizing Hebbian plasticity and memory?Nat. Rev. Neurosci. 1, 11–20.

    Article  PubMed  CAS  Google Scholar 

  • Berghuis P, MB Dobszay, X Wang, S Spano, F Ledda, KM Sousa, G Schulte, P Ernfors, K Mackie, G Paratcha, YL Hurd and T Harkany (2005) Endocannabinoids regulate interneuron migration and morphogenesis by transactivating the TrkB receptor.Proc. Natl. Acad. Sci. USA 102, 19115–19120.

    Article  PubMed  CAS  Google Scholar 

  • Berghuis P, AM Rajnicek, YM Morozov, RA Ross, J Mulder, GM Urban, K Monory, G Marsicano, M Matteoli, A Canty, AJ Irving, I Katona, Y Yanagawa, P Rakic, B Lutz, K Mackie and T Harkany (2007) Hardwiring the brain: endocannabinoids shape neuronal connectivity.Science 316, 1212–1216.

    Article  PubMed  CAS  Google Scholar 

  • Bernard C, M Milh, YM Morozov, Y Ben-Ari, TF Freund and H Gozlan (2005) Altering cannabinoid signaling during development disrupts neuronal activity.Proc. Natl. Acad. Sci. USA 102, 9388–9393.

    Article  PubMed  CAS  Google Scholar 

  • Caspi A, ET Mofitt, M Cannon, J McClay, R Murray, HL Harrington, A Taylor, L Arseneault, B Williams, A Braithwaite, R Poulton and IW Craig (2005) Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction.Biol. Psychiatry 57, 1117–1127.

    Article  PubMed  CAS  Google Scholar 

  • Chavarría-Siles I, J Contreras-Rojas, E Hare, C Walss-Bass, P Quezada, A Dassori, S Contreras, R Medina, M Ramírez, R Salazar, H Raventos and MA Escamilla (2008) Cannabinoid receptor 1 gene(CNR1) and susceptibility to a quantitative phenotype for hebephrenic schizophrenia.Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B(3), 279–284.

    Article  Google Scholar 

  • Cheer JF, KM Wassum, ML Heien, PE Phillips and RM Wightman (2004) Cannabinoids enhance subsecond dopamine release in the nucleus accumbens of awake rats.J. Neurosci. 24(18), 4393–4400.

    Article  PubMed  CAS  Google Scholar 

  • D’Souza DC, E Perry, L MacDougall, Y Ammerman, T Cooper, Y-T Wu, G Braley, R Gueorguieva, JH Krystalet al. (2004) The psychotomimetic effects of intravenous Δ-9-tetrahydrocannabinol in healthy individuals: implications for psychosis.Neuropsychopharmacology 29(8), 1558–1572.

    Article  PubMed  CAS  Google Scholar 

  • Day NL, L Goldschmidt and CA Thomas (2006) Prenatal marijuana exposure contributes to the prediction of marijuana use at age 14.Addiction 101, 1313–1322.

    Article  PubMed  Google Scholar 

  • Eggan SM and DA Lewis (2007) Immunocytochemical distribution of the cannabinoid CB1receptor in the primate neocortex: a regional and laminar analysis.Cereb. Cortex 17, 175–191.

    Article  PubMed  Google Scholar 

  • Fergusson DM, LJ Horwood and NR Swain-Campbell (2003) Cannabis dependence and psychotic symptoms in young people.Psychol. Med. 33, 15–21.

    PubMed  CAS  Google Scholar 

  • Freund TF, I Katona and D Piomelli (2003) Role of endogenous cannabinoids in synaptic signaling.Physiol. Rev. 83, 1017–1066.

    PubMed  CAS  Google Scholar 

  • Fried PA (2002) Conceptual issues in behavioral teratology and their application in determining long-term sequelae of prenatal marihuana exposure.J. Child Psychol. Psychiatry 43, 81–102.

    Article  PubMed  CAS  Google Scholar 

  • Fried PA and AM Smith (2001) A literature review of the consequences of prenatal marihuana exposure. An emerging theme of a deficiency in aspects of executive function.Neurotoxicol. Teratol. 23, 1–11.

    Article  PubMed  CAS  Google Scholar 

  • Fried PA, B Watkinson and R Gray (1992) A follow-up study of attentional behavior in 6-year-old children exposed prenatally to marihuana, cigarettes, and alcohol.Neurotoxicol. Teratol. 14, 299–311.

    Article  PubMed  CAS  Google Scholar 

  • Giuffrida A., LH Parsons, TM Kerr, F Rodriguez de Fonseca, M Navarro and D Piomelli (1999) Dopamine activation of endogenous cannabinoid signaling in dorsal striatum.Nat. Neurosci. 2, 358–363.

    Article  PubMed  CAS  Google Scholar 

  • Goldschmidt L, NL Day and GA Richardson (2000) Effects of prenatal marijuana exposure on child behavior problems at age 10.Neurotoxicol. Teratol. 22, 325–336.

    Article  PubMed  CAS  Google Scholar 

  • Goldschmidt L, GA Richardson, MD Cornelius and NL Day (2004) Prenatal marijuana and alcohol exposure and academic achievement at age 10.Neurotoxicol. Teratol. 26, 521–532.

    Article  PubMed  CAS  Google Scholar 

  • Gray KA, NL Day, S Leech and GA Richardson (2005) Prenatal marijuana exposure: effect on child depressive symptoms at ten years of age.Neurotoxicol. Teratol. 27, 439–448.

    Article  PubMed  CAS  Google Scholar 

  • Grech A, J Van Os, PB Jones, SW Lewis RM Murray (2005) Cannabis use and outcome of recent onset psychosis.Eur. Psychiatry 20(4), 349–353.

    Article  PubMed  Google Scholar 

  • Harkany T, M Guzman, I Galve-Roperh, P Berghuis, LA Devi and K Mackie (2007) The emerging functions of endocannabinoid signaling during CNS development.Trends Pharmacol. Sci. 28, 83–92.

    Article  PubMed  CAS  Google Scholar 

  • Harkany T, E Keimpema, K Barabas and J Mulder (2008) Endocannabinoid functions controlling neuronal specification during brain development.Mol. Cell. Endocrinol. 286, S84-S90.

    Article  PubMed  CAS  Google Scholar 

  • Henquet C, L Krabbendam, J Spauwen, C Kaplan, R Lieb, H-U Wittchenet al. (2005) Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people.BMJ 330(7481), 11. Epub 2004 Dec 1.

    Article  PubMed  Google Scholar 

  • Henquet C, R Murray, D Linszen and J van Os (2005) The environment and schizophrenia: the role of cannabis use.Schizophr. Bull. 31, 608–612.

    Article  PubMed  Google Scholar 

  • Henquet C, A Rosa, L Krabbendam, S Papiol, L Fananás, M Drukker, JG Ramaekers and J van Os (2006) An experimental study of catechol-O-methyltransferase Val158Met moderation of Δ-9-tetrahydrocannabinol-induced effects on psychosis and cognition.Neuropsychopharmacology 31(12), 2748–2755.

    Article  PubMed  CAS  Google Scholar 

  • Huizink AC and EJ Mulder (2006) Maternal smoking, drinking or cannabis use during pregnancy and neurobehavioral and cognitive functioning in human offspring.Neurosci. Biobehav. Rev. 30, 24–41.

    Article  PubMed  CAS  Google Scholar 

  • Kawamura Y, M Fukaya, T Maejima, T Yoshida, E Miura, M Watanabe, T Ohno-Shosaku and M Kano (2006) The CB1 cannabinoid receptor is the major cannabinoid receptor at excitatory presynaptic sites in the hippocampus and cerebellum.J. Neurosci. 26, 2991–3001.

    Article  PubMed  CAS  Google Scholar 

  • Kapur S, R Mizrahi and M Li (2005) From dopamine to salience to psychosis-linking biology, pharmacology and phenomenology of psychosis.Schizophr. Res. 79, 59–68.

    Article  PubMed  Google Scholar 

  • Laruelle M, A Abi-Dargham, CH van Dyck, R Gil, CD D’Souza, J Erdos, E McCance, W Rosenblatt, C Fingado, SS Zoghbi, RM Baldwin, JP Seibyl, JH Krystal, DS Charney and RB Innis (1996) Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects.Proc. Natl. Acad. Sci. USA 93, 9235–9240.

    Article  PubMed  CAS  Google Scholar 

  • Leech SL, GA Richardson, L Goldschmidt and NL Day (1999) Prenatal substance exposure: effects on attention and impulsivity of 6-year-olds.Neurotoxicol. Teratol. 21, 109–118.

    Article  PubMed  CAS  Google Scholar 

  • Leweke F, U Schneider, M Radwan, E Schmidt and HM Emrik (2000) Different effects of nabilone and cannabidiol on binocular bepth inversion in man.Pharmacol. Biochem. Behav. 66, 175–181.

    Article  PubMed  CAS  Google Scholar 

  • Mackie K, Y Lai, R Westenbroek and R Mitchell (1995) Cannabinoids activate an inwardly rectifying potassium conductance and inhibit Q-type calcium currents in AtT20 cells transfected with rat brain cannabinoid receptor.J. Neurosci. 15, 6552–6561.

    PubMed  CAS  Google Scholar 

  • Mátyás F, Y Yanovsky, K Mackie, W Kelsch, U Misgeld and TF Freund (2006) Subcellular localization of type 1 cannabinoid receptors in the rat basal ganglia.Neuroscience 137, 337–361.

    Article  PubMed  Google Scholar 

  • Mereu G, M Fa, L Ferraro, R Cagiano, T Antonelli, M Tattoli, V Ghiglieri, S Tanganelli, GL Gessa and V Cuomo (2003) Prenatal exposure to a cannabinoid agonist produces memory deficits linked to dysfunction in hippocampal long-term potentiation and glutamate release.Proc. Natl. Acad. Sci. USA 100, 4915–4920.

    Article  PubMed  CAS  Google Scholar 

  • Moore TH, S Zammit, A Lingford-Hughes, TR Barnes, PB Jones, M Burke and G Lewis (2007) Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review.Lancet 370(9584), 319–328.

    Article  PubMed  Google Scholar 

  • Morita Y, H Ujike, Y Tanaka, N Uchida, A Nomura, K Ohtani, M Kishimoto, A Morio, T Imamura, A Sakai, T Inada, M Harano, T Komiyama, M Yamada, Y Sekine, N Iwata, M Iyo, I Sora, N Ozaki and S Kuroda (2005) A nonsynonymous polymorphism in the human fatty acid amide hydrolase gene did not associate with either methamphetamine dependence or schizophrenia.Neurosci. Lett. 376(3), 182–187. Epub 2004 Dec 9.

    Article  PubMed  CAS  Google Scholar 

  • Mulder J, T Aguado, E Keimpema, K Barabas, CJ Ballester-Rosado, L Nguyen, K Monory, G Marsicano, V Di Marzo, YL Hurd, F Guillemot, K Mackie, B Lutz, M Guzman, HC Lu, I Galve-Roperh and T Harkany (2008) Endocannabinoid signaling controls pyramidal cell specification and long-range axon patterning.Proc. Natl. Acad. Sci. USA 105, 8760–8765.

    Article  PubMed  CAS  Google Scholar 

  • Seeman P, D Weinshenker, R Quirion, LK Srivastava, SK Bhardwaj, DK Grandy, RT Premont, TD Sotnikova, P Boksa, M El-Ghundi, B O’Dowd, F George, SR Perreault, ML Mannisto, PT Robinson, S Palmiter and RD Tallerico (2005) Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis.Proc. Natl. Acad. Sci. USA 102, 3513–3518.

    Article  PubMed  CAS  Google Scholar 

  • Seifert J, S Ossege, HM Emrich, U Schneider and M Stuhrmann (2007) No association of CNR1 gene variations with susceptibility to schizophrenia.Neurosci. Lett. 426(1), 29–33. Epub 2007Aug10.

    Article  PubMed  CAS  Google Scholar 

  • Spano MS, M Ellgren, X Wang and YL Hurd (2007) Prenatal cannabis exposure increases heroin seeking with allostatic changes in limbic enkephalin systems in adulthood.Biol. Psychiatry 61, 554–563.

    Article  PubMed  CAS  Google Scholar 

  • Stefanis NC, M Hanssen, NK Smirniset al. (2002) Evidence that three dimensions of psychosis have a distribution in the general population.Psychol. Med. 32, 347–358.

    Article  PubMed  CAS  Google Scholar 

  • Stefanis NC, P Delespaul, C Henquet, C Bakoula, CN Stefanis and J Van Os (2004) Early adolescent cannabis exposure and positive and negative dimensions of psychosis.Addiction 99, 1333–1341.

    Article  PubMed  CAS  Google Scholar 

  • Ujike H, M Takaki, K Nakata, Y Tanaka, T Takeda, M Kodama, Y Fujiwara, A Sakai and S Kuroda (2002) CNR1, central cannabinoid receptor gene, associated with susceptibility to hebephrenic schizophrenia.Mol. Psychiatry 7, 515–518.

    Article  PubMed  CAS  Google Scholar 

  • Uchigashima M, M Narushima, M Fukaya, I Katona, M Kano and M Watanabe (2007) Subcellular arrangement of molecules for 2-arachidonoyl-glycerol-mediated retrograde signaling and its physiological contribution to synaptic modulation in the striatum.J. Neurosci. 27, 3663–3676.

    Article  PubMed  CAS  Google Scholar 

  • United Nations Office on Drugs and Crime UNODC World Drug Report (2006) [online] http://www.unodc.org/unodc/ en/world_drug_report_2006.html.

  • Zuardi AW, I Shirakawa, E Finkelfarbet al. (1982) Action of cannabidiol on the anxiety and other effects produced by Δ9-THC in normal subjects.Psychopharmacol. (Berl.) 76, 245–250.

    Article  CAS  Google Scholar 

  • Zuardi AW, JA Rodrigues and JM Cunha (1991) Effects of cannabidiol in animal models predictive of antipsychotic activity.Psychopharmacol. (Berl.) 104(2), 260–264.

    Article  CAS  Google Scholar 

  • Zuardi AW, SL Morais, FS Guimarães and R Mechoulam (1995) Antipsychoticeffectofcannabidiol.J. Clin. Psychiatry 56(10), 485–486.

    PubMed  CAS  Google Scholar 

  • Zuardi AW, JEC Hallak, SM Dursunet al. (2006) Cannabidiol monotherapy for treatment-resistant schizophrenia.J Psychopharmacol. 20(5), 683–686. Epub 2006 Jan 9.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Psychological Medicine, Institute of Psychiatry, Denmark Hill, SE5 8AF, London, UK

    Sonija Luzi, Paul D. Morrison, John Powell, Marta Di Forti & Robin M. Murray

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  1. Sonija Luzi
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  2. Paul D. Morrison
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  3. John Powell
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  4. Marta Di Forti
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  5. Robin M. Murray
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Correspondence to Robin M. Murray.

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Luzi, S., Morrison, P.D., Powell, J. et al. What is the mechanism whereby cannabis use increases risk of psychosis?. neurotox res 14, 105–112 (2008). https://doi.org/10.1007/BF03033802

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